Kinase inhibitors

ABSTRACT

The present invention provides kinase inhibitors of Formula (I).

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinasefirst discovered as one of a number of kinases capable ofphosphorylating and inactivating glycogen synthase, the regulatoryenzyme of glycogen synthesis in mammals (Embi, et al., Eur. J. Biochem.,107, 519-527 (1980)). Existing in two isoforms, GSK-3α and GSK-3β, GSK-3phosphorylates a wide variety of proteins in vitro. The diversity ofthese proteins suggests a role for GSK-3 in the control of cellularmetabolism, growth, and development.

Type I diabetes is characterized by a lack of insulin resulting from thedestruction of insulin producing cells in the pancreas. Type II diabetesis characterized by defective insulin secretion and action. The bindingof insulin to its receptor initiates a cascade of events resulting inthe phosphorylation and inhibition of GSK-3, contributing to theinsulin-induced stimulation of glycogen and protein synthesis.Inhibitors of GSK-3 have been shown to mimic the actions of insulin(Coghlan, et al., Chem. Biol., 7, 793-803 (2000)), including the abilityto lower blood glucose levels in vivo (Norman, Drug News Perspect., 14,242-247 (2001)). These recent discoveries suggest that inhibitors ofGSK-3 have a potential role in the treatment of diabetes.

Alzheimer's disease is characterized by the micro-tubule-associatedprotein Tau existing in an abnormally hyperphosphorylated state (Cohenand Frame, Nature Reviews: Molecular Cell Biology, 2, 769-776 (October2001) <www.nature.com/reviews/molcellbio>). GSK-3 phosphorylates many ofthe hyperphosphorylated sites on Tau in vitro, preventing it frombinding to microtubules, making it available to undergo the aberrantfilament assembly that may underlie the neuronal degeneration observedin Alzheimer's disease and other neurological disorders. Inhibitors ofGSK-3, such as insulin and lithium ions, have been shown to induce apartial dephosphorylation of Tau in neuronal cells (Cross, et al., J.Neurochem., 77, 94-102 (2001)). These discoveries suggest thatinhibitors of GSK-3 have a potential role in the treatment ofdegenerative neurological disorders such as Alzheimer's disease.

WO 98/16528 describes purine derivatives, WO 99/65897 describespyrimidine and pyridine derivatives, WO 00/38675 describes maleimides,and WO 01/56567 describes diaminothia-zole derivatives that are taughtto be inhibitors of GSK-3. Additional GSK-3 inhibitors are necessary toprovide treatments for GSK-3 mediated endocrine and neurologicaldisorders. The present invention provides inhibitors of GSK-3.

The present invention provides compounds of Formula I:

where:

-   -   Ar is benzofur-7-yl optionally substituted in the phenyl ring        with R⁸ and R⁹, 1-(R⁷)-indol-4-yl, benzofur-4-yl, quinolin-5-yl,        quinolin-7-yl, isoquinolin-5-yl, isoquinolin-3-yl,        imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl,        furo[3,2-c]pyridin-7-yl, benzo[1,3]dioxol-4-yl,        2,2-difluorobenzo[1,3]dioxol-4-yl, or 2,3-dihydrobenzofur-7-yl        optionally substituted in the phenyl ring with R⁸ and R⁹ and in        the dihydrofuryl ring with C₁-C₄ alkyl;    -   R^(1a) is hydrogen, C₁-C₄ alkoxy, —(CH₂)_(m)-G, O—(CH₂)_(m)-G,        halo, C₁-C₄ alkyl optionally substituted with one to three halo,        piperazin-1-yl optionally substituted 1-2 times with        —(CO₂)_(n)—(C₁-C₄ alkyl), or —(CH₂)—O—(CH₂)—O—(CH₃);    -   R^(1b) is hydrogen or halo;    -   R^(1c) is hydrogen or halo;    -   G is independently at each occurrence hydroxy, NR¹¹R¹², or        piperidin-4-yl;    -   R² is hydrogen, C₁-C₄ alkyl, —(CH₂)_(m)-G, tetrahydropyran-4-yl,        4-(NR⁴R⁵)cyclohex-1-yl, 4-hydroxycyclohex-1-yl,        2-azabicyclo[3.2.1]oct-5-yl, the moiety    -    the moiety    -    cyclohexan-1-on-4-yl, pyridin-4-yl; and R³ is hydrogen, halo,        C₁-C₄ alkyl, or cyclopropyl; or R² and R³ taken together        represent    -   R⁴ is hydrogen and R⁵ is hydrogen or C₁-C₄ alkyl, or R⁴ and R⁵        taken together with nitrogen to which they are attached form a        pyrrolidine ring;    -   R⁶ is hydrogen, benzyl, —CO₂(C₁-C₄ alkyl), —C(O)—(C₁-C₄        alkyl)_(n)—NR¹⁴R¹⁵, —C(O)tetrahydropyran-4-yl,        —C(O)morpholin-4-yl, —CH₂-tetrahydropyran-4-yl, an amino acid        residue, —C(O)pyridin-2-yl, —C(O)pyridin-3-yl, —C(O)pyridinyl,        —C(O)pyrimidin-5-yl, C₁-C₄ alkyl, —C(O)pyrazin-2-yl, or        —CO₂—(C₁-C₄ alkyl)-(C₁-C₄ alkoxy);    -   R⁷ is hydrogen, C₁-C₄ alkyl, or —(CH₂)_(m)-G;    -   R⁸ is —NHCO₂(C₁-C₄ alkyl), —NHSO₂(C₁-C₄ alkyl), halo, amino,        —O—(CH₂)_(m)-G, —NHC(O)(C₁-C₄ alkyl), C₁-C₄ alkoxy, hydroxy,        —O—R¹⁰, C₁-C₄ alkyl, C₁-C₄ alkylthio, or —(CH₂)_(m)-G;    -   R⁹ is halo;    -   R¹⁰ is piperidin-3-yl, piperidin-4-yl, or pyrrolidin-3-yl;    -   R¹¹ and R¹² are independently selected from the group consisting        of hydrogen, C₁-C₄ alkyl, cyclopropylmethyl, benzyl, or, taken        together with the nitrogen to which they are attached form a        piperidine, 4-hydroxypiperidine, 4-(C₁-C₄ alkyl)piperidine,        N—(R¹³)-piperazine, or morpholine ring;    -   R¹³ is hydrogen, C(O)—(C₁-C₄ alkyl), or C₁-C₄ alkyl;    -   R¹⁴ and R¹⁵ are independently hydrogen or C₁-C₄ alkyl;    -   R¹⁶ is independently at each occurrence hydrogen, geminal        dimethyl, geminal diethyl, a spiro-fused C₃-C₆ cycloalkyl, or        C₁-C₄ alkyl optionally substituted with hydroxy; and R¹⁷        represents hydrogen, C₁-C₄ alkyl, or geminal dimethyl, provided        that the total number of carbon atoms between R¹⁶ and R¹⁷ does        not exceed five;    -   m is independently at each occurrence 2, 3, 4, or 5;    -   n is independently at each occurrence 0 or 1; or        pharmaceutically acceptable salt thereof, subject to the        following provisos:    -   i) when G is hydroxy, no more than two of R^(1a), R², R⁷, or R⁸        may be —(CH₂)_(m)-G, or —O—(CH₂)_(m)-G; and    -   ii) when G is NR¹¹R¹², no more than one of R^(1a), R², R⁷, or R⁸        may be —(CH₂)_(m)-G, or —O—(CH₂)_(m)-G.

The present invention also provides a method of treating diabetes in amammal comprising administering to a mammal in need of such treatment aneffective amount of a compound of Formula I.

The present invention also provides a method of treating Alzheimer'sdisease in a mammal comprising administering to a mammal in need of suchtreatment an effective amount of a compound of Formula I.

The present invention further provides a method of inhibiting GSK-3 in amammal comprising administering to a mammal in need of such treatment aneffective amount of a compound of Formula I.

The present invention also provides a pharmaceutical formulationcomprising a compound of Formula I, in combination with apharmaceutically acceptable carrier, diluent or excipient.

The present invention further provides a method of stimulating bonedeposition in a mammal comprising administering to a mammal in need ofsuch treatment an effective amount of a GSK-3 inhibitor.

The present invention also provides a method of stimulating bonedeposition in a mammal comprising administering to a mammal in need ofsuch treatment an effective amount of a compound of Formula I.

Furthermore, this invention provides the use of a compound of Formula Ifor the manufacture of a medicament for the treatment of diabetes. Thisinvention also provides the use of a compound of Formula I for themanufacture of a medicament for the treatment of Alzheimer's disease.This invention also provides the use of a compound of Formula I for themanufacture of a medicament for the inhibition of GSK-3.

This invention also provides the use of a compound of Formula I for themanufacture of a medicament for the inhibition of GSK-3. Additionally,this invention provides a pharmaceutical formulation adapted for thetreatment of diabetes containing a compound of Formula I. Furthermore,this invention provides the use of a compound of Formula I for themanufacture of a medicament for the treatment of diabetes. Thisinvention also provides the use of a compound of Formula I for themanufacture of a medicament for the treatment of Alzheimer's disease.The present invention also provides a formulation adapted forstimulating bone deposition in mammals containing a compound of Formula.The present invention further provides the use of a compound of FormulaI for the manufacture of a medicament for stimulating bone deposition.

The following definitions are to set forth the meaning and scope of thevarious terms used herein. The general terms used herein have theirusual meanings.

The term “GSK-3” refers to GSK-3α and/or GSK-3β.

The term “diabetes” is taken to mean Type I and/or Type II diabetes.

The term “effective amount” as used in “an effective amount of acompound of Formula I,” for example, refers to an amount of a compoundof the present invention that is capable of inhibiting GSK-3.

The general chemical terms used herein have their usual meanings. Forexample, as used herein, the term “C₁-C₄ alkyl,” alone or incombination, denotes a straight-chain or branched-chain C₁-C₄ alkylgroup consisting of carbon and hydrogen atoms, examples of which aremethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and thelike. The term “geminal dimethyl” represents two methyl groups attachedat the same substitution position. The term “C₃-C₆ cycloalkyl” refers tocyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term“spiro-fused C₃-C₆ cycloalkyl” refers to a C₃-C₆ cycloalkyl group asdefined above bonded to a carbon atom through a spiro linkage.

The term “C₁-C₄ alkoxy,” alone or in combination, denotes an alkyl groupas defined earlier which is attached via an oxygen atom, such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, andthe like. The term “C₁-C₄ alkylthio,” alone or in combination, denotesan alkyl group as defined earlier which is attached via a sulfur atom,and includes methylthio, ethylthio, isobutylthio, and the like.

The term “hydroxy,” alone or in combination, represents an —OH moiety.As used herein, the term “halo” or “halogen” represents fluorine,chlorine, bromine, or iodine.

The term “amino acid residue” is taken to mean an amino acid moietyselected from the group consisting of alanyl, arginyl, asparaginyl,aspartyl, cysteinyl, glutaminyl, glutamyl, glycyl, histidyl, isoleucyl,leucyl, lysyl, methionyl, phenylalanyl, phenylglycyl, prolyl, seryl,threonyl, tryptophanyl, tyrosyl, and valyl bonded through an acidcarbonyl.

It will be understood by the skilled reader that most or all of thecompounds of the present invention are capable of forming salts. In allcases, the pharmaceutically acceptable salts of all of the compounds areincluded in the names of them. The compounds of the present inventionare amines, and accordingly react with any of a number of inorganic andorganic acids to form pharmaceutically acceptable acid addition salts.Preferred pharmaceutically acceptable salts are those formed withhydrochloric acid.

Although all of the compounds of Formula I are useful GSK-3 inhibitors,certain compounds are preferred. The following paragraphs definepreferred classes.

-   -   a) Ar is benzofur-7-yl.    -   b) Ar is 2,3-dihydrobenzofur-7-yl optionally substituted in the        phenyl ring with halo.    -   c) Ar is 2,3-dihydro-6-fluorobenzofur-7-yl.    -   d) Ar is imidazo[1,2-a]pyridin-3-yl.    -   e) R^(1a) is —(CH₂)_(m)-G.    -   f) R^(1a) is —(CH₂)_(m)-G.    -   g) R^(1b) is hydrogen.    -   h) R^(1b) is fluoro.    -   i) R^(1c) is hydrogen.    -   j) R^(1c) is fluoro.    -   k) G is hydroxy.    -   l) G is NR¹¹R¹²    -   m) G is piperidin-4-yl.    -   n) R² is —(CH₂)_(m)-G.    -   o) R² is 1-(R⁶)-piperidin-4-yl.    -   p) R² is 1-(R⁶)-piperidin-4-yl further substituted with methyl.    -   q) R³ is halo.    -   r) R² and R³ taken together represent    -   s) R⁶ is hydrogen.    -   t) R⁶ is —C(O)morpholin-4-yl.    -   u) R⁶ is —C(O) pyrazin-2-yl.    -   v) R⁷ is methyl.    -   w) R⁷ is —(CH₂)_(m)-G.    -   x) R⁸ is —O—(CH₂)_(m)-G.    -   y) R⁸ is halo.    -   z) R⁸ is fluoro.    -   aa) R⁹ is methoxy.    -   bb) R⁸ is hydroxy.    -   cc) R⁹ is fluoro.    -   dd) R⁹ is chloro.    -   ee) R¹¹ is hydrogen.    -   ff) R¹¹ is methyl.    -   gg) R¹¹ is ethyl.    -   hh) R¹² is hydrogen.    -   ii) R¹² is methyl.    -   jj) R¹² is ethyl.    -   kk) R¹³ is hydrogen.    -   ll) R¹⁴ and R¹⁵ both are hydrogen.    -   mm) R¹⁴ is hydrogen and R¹⁵ is methyl.    -   nn) R⁶ is methyl.    -   oo) R¹⁶ is geminal dimethyl.    -   pp) R¹⁷ is geminal dimethyl.    -   qq) The compound is a free base.    -   rr) The compound is a salt.    -   ss) The compound is the hydrochloride salt.

The preceding paragraphs may be combined to define additional preferredclasses of compounds.

The compounds of Formula I are inhibitors of GSK-3. Thus, the presentinvention also provides a method of inhibiting GSK-3 in a mammal thatcomprises administering to a mammal in need of said treatment a GSK-3inhibiting amount of a compound of Formula I. The present compounds arebelieved to be useful in treating Type I and/or Type II diabetes.Furthermore, the compounds of the present invention are believed to beuseful in the treatment of neurological disorders such as dementias,especially dementia of the Alzheimer's type. The compounds of thepresent invention are also believed to be useful for the treatment ofbipolar disorder.

A further embodiment of the present invention is the use of inhibitorsof GSK-3 for rapid bone deposition. This ability to stimulate rapid bonedeposition provides a new means to treat a variety of disease states andconditions where it would be beneficial to grow new bone. These diseasestates include osteoporosis and fraility as well as bone loss due toperiodontal disease. Compounds exhibiting this activity will also beuseful in promoting wound healing and bone fracture repair. It is alsocontemplated that GSK-3 inhibitor mediated bone deposition will improvepatient outcomes in joint replacement surgeries by enhancing theattachment of a joint prosthesis to the patient's bone. The use of thecompounds of the present invention for the induction of rapid bonedeposition is preferred. It is preferred that the mammal to be treatedby the administration of the compounds of Formula I is human.

The skilled artisan will appreciate that the introduction of certainsubstituents will create asymmetry in the compounds of Formula I. Thepresent invention contemplates all enantiomers and mixtures ofenantiomers, including racemates. It is preferred that the compounds ofthe invention containing chiral centers are single enantiomers.

The compounds of the present invention can be prepared by a variety ofprocedures, some of which are illustrated in the Schemes below. It willbe recognized by one of skill in the art that the individual steps inthe following schemes may be varied to provide the compounds of FormulaI. The particular order of steps required to produce the compounds ofFormula I is dependent upon the particular compound being synthesized,the starting compound, and the relative lability of the substitutedmoieties. Some substituents—such as R^(1a), R^(1b), and R^(1c)—have beeneliminated in the following schemes for the sake of clarity and are notintended to limit the teaching of the schemes in any way.

Scheme I depicts synthetic methods for the formation of thebisarylmaleimides of Formula I via Methods A and B. This reaction iswell known in the art. See, for example, Faul, et al., J. Org. Chem. 63,6053-6058 (1998). The oxoacetic acid esters of formula (1) or (4), arereacted with the acetamides of formula (2) or (3), respectively, in asuitable solvent, such as dimethylformamide or tetrahydrofuran, in thepresence of a suitable base, such as sodium hydride or preferablypotassium tert-butoxide. The reaction is conducted at 0° C. to roomtemperature, and the reactants are stirred for 1-24 hours. The reactionmixture is treated with a suitable acid, such as hydrochloric acid,after which the mixture is stirred at about ambient temperature for 1-24hours. The resulting maleimides of Formula I may be isolated by standardtechniques, and purified by crystallization or chromatography asnecessary or desired.

The requisite oxoacetic acid esters of formulae (1) and (4) can beprepared from appropriately substituted indoles and aryl groups. Theformation of oxoacetic acid esters is depicted in Schemes IIa and IIb.

The 3-indolyloxoacetic acid esters of formula (1) are eithercommercially available or may be prepared as depicted in Scheme IIa. Anappropriately substituted indole is reacted with an oxalyl halide, suchas oxalyl chloride, in the presence of an organic base, such as2,6-lutidine or triethylamine, in an appropriate solvent, such asdichloromethane or diethyl ether, to give a compound of formula (1). Thereaction is performed at low temperatures, and the mixture is stirredfor 1-24 hrs. When an oxalyl halide is used, the mixture is furthercooled to about −78° C. and an alkoxide source, such as sodiummethoxide, is added in with an appropriate solvent, such as methanol.The resulting oxoacetic acid ester may be isolated by standardtechniques and purified by crystallization or chromatography asnecessary or desired. The formation of formula (1) in Scheme II is wellknown in the art; see, for example, Faul, et al., J. Org. Chem. 63,6053-6058 (1998).

In Scheme IIb, compounds of formula (4) are prepared from appropriatelysubstituted halogenated-aryls of formula (11) where X is halo. Acompound of formula (11) is subjected to a lithium-halogen exchange,following which the lithium anion is quenched by an oxalate, such as adialkyl oxalate, as described in Scheme IIa, to give compounds offormula (4). The skilled artisan would also recognize the use of aGrignard reagent quenched with the oxalate at low temperatures as analternate synthetic method

The formation of acetamides is depicted in Scheme III.

In Scheme IIIa, the compounds of formula (11) are converted to compoundsof formula (12) in step i by lithium-halogen exchange, followed byquenching with N,N-dimethylformamide. Compounds of formula (13) areformed in step f, via a phosphorylated cyanohydrin formed in situ fromreaction of compounds of formula (12), diethylcyanophosphonate, andlithium cyanide in a suitable solvent, such as tetrahydrofuran. Forsimilar examples of this conversion see, Yoneda, et al, TetrahedronLett. 30, 3681-3684 (1989); Yoneda, et al., J. Org. Chem., 56, 1827-1832(1991). Base hydrolysis of the acetonitrile group, step g, gives theacetamides of formula (3).

Also, the skilled artisan would appreciate, as an alternative method,the use of 2-ethoxy-2-oxoethylzinc bromide, with a palladium catalyst,in a suitable solvent, such as tetrahydrofuran, to give compounds offormula (14) via step j. Compounds of formula (14) can then be subjectedto base hydrolysis conditions in step k to give compounds of formula(15). Compounds of formula (15) are converted to compounds of formula(2) in step 1 under standard coupling conditions in the presence of aammonium source, such as ammonium hydroxide or ammonia gas. Suitablecoupling reagents include N,N′-carbonyldiimidazole (CDI),N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), and1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (PEPC). Suitableoptional catalysts for the coupling reaction includeN,N-[dimethyl]-4-aminopyridine (DMAP). All of the reagents are combinedin a suitable solvent—typically dichloromethane, chloroform,tetrahydrofuran, dioxane, or diethyl ether—and are stirred for from 1 to72 hours at a temperature of from ambient to about the refluxtemperature of the solvent. The desired product may be isolated bystandard extractive and crystallization techniques, and purified bychromatography or crystallization as necessary or desired.

Alternatively, in step m, the skilled artisan would appreciate thatcompounds of formula (14) may be reacted to form compounds of formula(2) directly. A compound of formula (14) in a suitable solvent, such asmethanol, that has been saturated with ammonia gas, is placed in asealed container and reacted at elevated temperatures to form compoundsof formula (2).

The requisite aryl intermediates for the formation of formula (2) or (4)are commercially available or can be synthetically prepared as describedherein.

Conversions of compounds of formula (10) to compounds of formula(3)—involving base hydrolysis of an appropriately substituted indoleacetonitrile, similar to step g of Scheme IIIa—are well known andappreciated in the art; see, for example, Larock, Comprehensive OrganicTransformations, 2^(nd) Ed., John Wiley & Sons, New York, pg. 1988-1989(1999). The resulting 3-indolylacetamide of formula (3) can be isolatedby standard techniques and may be purified by crystallization orchromatography as necessary or desired. This reaction producesappropriately 3-substituted-indoles.

Benzofurans of formula (18) may be derived from compounds of formula(16). As shown in step n, appropriately substituted phenols areO-alkylated with bromoacetaldehyde and a suitable base, such aspotassium carbonate. Cyclization is accomplished in a suitable solvent,in which water can be an azeotrope, such as chlorobenzene at refluxingtemperatures in step o.

Compounds of formula (21) may be formed as shown in Scheme V. Step pdepicts a [2+3] cyclization of optionally substituted 2-aminopyridinewith ethyl oxybutenoate in acetonitrile under reflux conditions toafford compounds of formula (20). Formula (20) can be transformed to theacetamide, formula (21), as previously described in step m.

The procedure of Scheme VI is a conversion ofN-methyl-pyrrole-2,5-diones, formula (5), to the correspondingfuran-2,5-dione, formula (6). This reaction, as shown in step b, can beperformed by a suitable base in which both formulae (5) and (6) aresynthetic stable intermediates used for the manipulation of the Rsubstituent groups. The furan-diones of formula (6) can be convertedinto the 1H-pyrrole-2,5-diones of Formula (I) in step c by the use of analkyl-disilazane reagent. Conversions of this type are well known in theart; see, for example, Davis, et al., Tetrahedron Lett., 31(36),5201-5204 (1990); and Mayer, et al., Tetrahedron Lett., 37(26),4483-4486 (1996).

The requisite indoles for Schemes IIa and IIIb are either commerciallyavailable or may be prepared by methods well known in the art. Indolesyntheses are described in Robinson, The Fischer Indole Synthesis, JohnWiley & Sons, New York (1983); Hamel, et al., J. Org. Chem., 59, 6372(1994); and Russell, et al., Org. Prep. and Procedures Intl., 17, 391(1985).

Many of the compounds of the present invention are not only inhibitorsof GSK-3, but are also useful intermediates for the preparation ofadditional compounds of the present invention. For example, secondaryamines may be acylated, alkylated or coupled with simple carboxylicacids or amino acids under standard conditions. Furthermore, estermoieties may be reduced to the corresponding alcohols. These alcoholsmay then be activated and displaced by a number of nucleophiles toprovide other compounds of the invention.

A skilled artisan would recognize several other transformations that canbe applied to the synthetic process for production of useful andreactive intermediates for the preparation of additional compounds ofthe present invention. Such transformations include but are not limitedto nucleophilic displacement of halogen with an appropriate amine (seeLarock, Comprehensive Organic Transformation, 2^(nd) Ed., John Wiley &Sons, New York, pg. 779-780 (1999)), alkylation or acylations of theappropriate amine, O-alkylation of the hydroxy intermediates, orhydroxy-halogen exchange (Larock, Comprehensive Organic Transformations,2^(nd) Ed, John Wiley & Sons, New York, pg. 689-697 (1999)). Further,compounds may be reacted with an appropriate reagent to introduce asuitable amino protecting group such as a formyl group, acetyl group, orpreferably a tert-butoxycarbonyl moeity. Techniques for the introductionof these groups are well known to the skilled artisan.

Additionally, in order to substitute alcohol derivatives with acorresponding amine, the skilled artisan would appreciate that necessaryintermediates would incorporate certain appropriate leaving groups. Suchleaving groups include but are not limited to halides, oxonium ions,alkyl perchlorates, ammonioalkaesulfonate esters, alkylfluorosulfonates, nonaflates, tresylates, triflates, and sulfonicesters, preferably the mesylate or tosylate. Techniques for theintroduction of these groups are also well known to the skilled artisan;see, for example, March, Advanced Organic Chemistry, 5^(th) Ed., JohnWiley and Sons, New York, pg. 445-449 (2001). The skilled artisan willappreciate that the nitrogen-protecting groups may be removed at anyconvenient point in the synthesis of the compounds of the presentinvention. Methods of formation and removal of an amino-protecting groupare well known in the art; see, for example, Greene and Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) Ed., John Wiley and Sons, New York,Chapter 7 (1999).

The skilled artisan will also appreciate that not all of thesubstituents in the compounds of Formula I will tolerate certainreaction conditions employed to synthesize the compounds. These moietiesmay be introduced at a convenient point in the synthesis, or may beprotected and then deprotected as necessary or desired. Furthermore, theskilled artisan will appreciate that in many circumstances, the order inwhich moieties are introduced is not critical. The particular order ofsteps required to produce the compounds of Formula I is dependent uponthe particular compound being synthesized, the starting compound, andthe relative lability of the substituted moieties.

The following preparations and examples further illustrate thepreparation of compounds of the present invention and should not beinterpreted in any way as to limit the scope. Those skilled in the artwill recognize that various modifications may be made while notdeparting from the spirit and scope of the invention. All publicationsmentioned in the specification are indicative of the level of thoseskilled in the art to which this invention pertains.

The terms and abbreviations used in the instant Preparations andExamples have their normal meanings unless otherwise designated. Forexample “° C.”, “N”, “mmol”, “g”, “mL”, “M”, “HPLC”, “IR”, “MS(FD)”,“MS(IS)”, “MS(FIA)”, “MS(FAB)”, “MS(EI)”, “MS(ES)”, “UV”, and “¹H NMR”,refer to degrees Celsius, normal or normality, millimole or millimoles,gram or grams, milliliter or milliliters, molar or molarity, highperformance liquid chromatography, infra red spectrometry, fielddesorption mass spectrometry, ion spray mass spectrometry, flowinjection analysis mass spectrometry, fast atom bombardment massspectrometry, electron impact mass spectrometry, electron spray massspectrometry, ultraviolet spectrometry, and proton nuclear magneticresonance spectrometry respectively. In addition, the absorption maximalisted for the IR spectra are only those of interest and not all of themaxima observed.

Preparation of Oxoacetic Acid Methyl Ester Intermediates:

Preparation 1 2-(1H-Indol-7-yl)-ethanol a)2-(2-nitrophenyl)-1-(tert-butyldimethylsilyloxy) ethane

Add 2-nitrophenethyl alcohol (20 g, 120 mmol) and imidazole (11.4 g, 167mmol) to dichloromethane (200 mL). Cooled to 0° C. and add solidtert-butyldimethylsilyl chloride (23.4 g, 155 mmol). Stir the mixture at20° C. for 2 hours and dilute with 1:1 ethyl acetate:diethyl ether. Washwith distilled water, aqueous 3% acetic acid, aqueous 0.5 molar sodiumhydrogen carbonate, and saturated sodium chloride. Dry over anhydrousmagnesium sulfate, filter, and concentrate under reduced pressure togive 32.4 g (96%) of the title compound as a light yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 7.89 (dd, 1H, J=8.0, 1.2 Hz), 7.50 (dt, 1H, J=7.2,1.6 Hz), 7.37 (m, 2H), 3.89 (t, 2H, J=6.4 Hz), 3.12 (t, 2H, J=6.4 Hz),0.83 (s, 9H), 0.06 (s, 61.

b) 2-(1H-Indol-7-yl)ethanol

Slowly add a 1.0 molar solution of vinylmagnesium bromide intetrahydrofuran (430 mL, 430 mmol) to a stirred solution of2-(2-nitrophenyl)-1-(tert-butyldimethylsilyloxy) ethane (27.4, 97.3mmol) in anhydrous tetrahydrofuran (300 mL) under nitrogen, maintainingthe internal temperature of the reaction between −48° C. and −43° C.Stir at −45° C. for 45 minutes. Pour into 1.5 liters of stirring aqueoussaturated ammonium chloride and extract with 50% hexane, 50% diethylether. Dry over anhydrous magnesium sulfate, filter, and concentrateunder reduced pressure. Chromatography on flash silica using a gradientfrom neat hexane to 7% ethyl acetate in hexane gives 14.4 g of a brownoil, which is a mixture of the tert-butyldimethylsilyl protected productand starting material.

Dissolve the brown oil in tetrahydrofuran (500 mL), add distilled water(100 mL), and cool the mixture to 15° C. Add 1M aqueous hydrochloricacid (100 mL), then stir at 15° C. for 2 hours. Add solid sodiumhydrogen carbonate until the reaction mixture is basic, and saturate byadding solid sodium chloride. Separate, filter, and concentrate underreduced pressure to obtain 9.3 of a brown oil, which is a mixture of thetitle compound and 2-nitrophenethyl alcohol.

Dissolve the brown oil in tetrahydrofuran (100 mL), add absolute ethanol(50 mL), then add 10% palladium on carbon, and stir the mixture underhydrogen (1 atm) at 20° C., for 2 hours. Dilute the mixture with ethylacetate and filter through a pad of Celite®. Wash with 0.2M aqueoushydrochloric acid, aqueous saturated sodium hydrogen carbonate, andsaturated sodium chloride. Dry over anhydrous magnesium sulfate, filter,concentrate under reduced pressure. Chromatography on flash silica usingethyl acetate, hexane gives 6.9 g (44%) of the title compound as anoff-white solid. HRMS(M+H)=162.0924.

Preparation 2 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-4-fluoro-1H-indole a)N-(endo-8-Carbethoxy-azabicyclo[3.2.1]octan-3-yl)-indole

Dissolve N-Carbethoxy-4-tropinone (11.97 g, 60.71 mmol) and2-(2,2-dimethoxyethyl)phenylamine (10.0 g, 55.19 mmol) in acetic acid(60 mL) and treat with sodium triacetoxyborhydride (17.54 g, 82.78mmol). Stir for 4 days at room temperature and than at 70° C. for 6 h.Wash with water (400 mL) and sodium hydroxide, extracting with ethylacetate. Dry the organic layer over sodium sulphate and evaporate.Purified the remaining oil by flash chromatography(dichloromethane/ethanol 95:5) to afford 13.36 g (34%) of the titlecompound as white crystals. MS: 299.1 M⁺+1.

b) 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-4-fluoro-1H-indole

Dissolve 2-(2′,2′-dimethoxyethyl)-3-fluorophenylamine (10 g, 50.2 mmol)and 1,4-cyclohexanedione monoketal (8.62 g, 55.2 mmol) in glacial aceticacid (100 mL), add sodium triacetoxyborohydride (15.96 g, 75.3 mmol) andheat the mixture to 70° C. for 20 h. Cool the reaction mixture in an icebath and made basic with 5N sodium hydroxide solution. Extract themixture with methylene chloride, wash with water, brine and dry oversodium sulphate to yield a yellow brown oil (14 g). Flash chromatographyusing a gradient of ethyl acetate in hexanes yields the pure product asa solid (11.14 g, 77.14%). ESMS m/z (relative intensity) 276.2 (M⁺+1,100).

Preparation 3 1-(2,2-Dimethoxyethyl)-3-methyl-2-nitrobenzene

Combine 2-nitro-meta-xylene (5 mL, 0.037 mol), N,N-dimethylformamidedimethylacetal (5.4 mL, 1.1 eq) and N,N-dimethylformamide (60 mL) in aflask and reflux under nitrogen for 2 days. Let cool to room temperaturethen concentrate to approximately one-half volume. Add methanol (40 mL)and trimethylsilylchloride (6.6 mL, 1.4 eq). Reflux overnight. Dilutewith ethyl acetate after cooling to room temperature then extract withsaturated sodium bicarbonate followed by brine. Dry over magnesiumsulfate, filter and concentrate. Purification by column chromatography(9:1 Hexanes:ethyl acetate) gives 1.15 g (14%) product as a light yellowoil. ¹H NMR (400 MHz, DMSO-d₆) δ 2.23 (s, 3H), 2.80 (d, J=5.36 Hz, 2H),3.19 (s, 6H), 4.45 (m, 1H), 7.32 (m, 2H), 7.42 (m, 1H).

Preparation 4 2-(2,2-Dimethoxyethyl)-6-methylaniline

Add to a round bottomed flask containing1-(2,2-dimethoxyethyl)-3-methyl-2-nitrobenzene (1.1 g) in methanol (50mL), 10% palladium on carbon (0.13 g). Purge with nitrogen then placeunder a hydrogen atmosphere using a balloon of hydrogen. Stir overnightat room temperature. Filter through Celite, wash with methanol.Concentrate to give product (0.98 g, 103%) as a clear oil. ¹H NMR (400MHz, DMSO-d₆) δ 2.05 (s, 3H), 2.71 (d, J=5.36 Hz, 211), 3.23 (s, 6H),4.52 (m, 3H), 6.42 (m, 1H), 6.80 (d, J=7.31 Hz, 2H).

Preparation 5 1-ethoxy-2-oxoethylzinc bromide

Mix acid washed zinc dust (3.28 g, 50.06 mmol) and cuprous chloride (0.5g, 5.06 mmol) in anhydrous tetrahydrofuran (10 mL) and reflux for 40min. Warm to room temperature and add ethyl bromoacetate (2.09 g, 1.4mL, 12.52 mmol). Stir mixture for 1 h and let stand (without stirring)overnight to facilitate settling of the zinc. Filter the reagentsolution before use.

Preparation 6 5-Methyl-1H-indole-7-carboxaldehyde a)5-Methyl-2-nitrobenzaldehyde

Dissolve (5-methyl-2-nitrophenyl)methanol (10 g, 59.88 mmol) indichloromethane (210 mL). Add 3 Å molecular sieves (54 g) and pyridiniumdichromate (22.53 g, 59.88 mmol). Stir at room temperature for 6 hours.Pass the crude reaction mixture through a short silica gel column, andremove under reduced pressure. Purification of the residue by flashchromatography (silica gel, 10-20% ethyl acetate:hexane) gives 7.84 g(79%) of title compound as colorless oil. ¹H NMR (CDCl₃) δ 10.41 (m,1H), 8.02 (m, 1H), 7.69 (s, 1H), 7.53 (d, 1H), 2.51 (s, 3H).

b) 2-Dibutoxymethyl-4-methyl-1-nitrobenzene

Dissolve 5-methyl-2-nitrobenzaldehyde (7.84 g, 47.52 mmol), 1-butanol(10.55 g, 142.6 mmol) and toluene-4-sulfonic acid (0.5 g) in toluene(200 mL). Heat to reflux, and remove the water using a Dean-Starkapparatus. Heat for 3 hours. Add water, and extract the aqueous layerwith ethyl acetate. Combine the organic layers, dry over sodium sulfate,filter, concentrate under reduced pressure, and purify by flashchromatography (1% v/v triethylamine buffered silica gel, 5% ethylacetate/hexane) to give 14 g (99%) of the title compound as colorlessoil.

c) 5-Methyl-1H-indole-7-carboxaldehyde

Dissolve 2-dibutoxymethyl-4-methyl-1-nitrobenzene (13.957 g, 47.373mmol) in anhydrous tetrahydrofuran (474 mL) under nitrogen, and cool to−40° C. Add vinylmagnesium bromide (190 mL, 190 mmol, 1.0 M intetrahydrofuran) at −40° C. with stirring. Stir for 40 minutes and addsaturated aqueous ammonium chloride. Extract the aqueous layer isextracted with ethyl acetate. Combine the organic layers, dry oversodium sulfate, filter, and concentrate. The crude product is taken onthe next step without purification.

Dissolve the crude product from above in tetahydrofuran (160 mL) andcool to 0° C. Add aqueous molar hydrochloric acid (20 mL) and stir themixture at 0° C. for 1 hour. Add saturated aqueous sodium hydrogencarbonate (200 mL) and extract the aqueous layer with ethyl acetate(3×200 mL). Combine the organic layers, dry over anhydrous sodiumsulfate, filter, concentrate under reduced pressure, and purify by flashcolumn chromatography (silica gel, 5% ethyl acetate/hexane) to give 4.04g (54% for 2 steps) of the title compound as a white solid. ¹H NMR(CDCl₃) δ 10.10 (s, 1H), 10.06 (s, 1H), 7.72 (s, 1H), 7.40 (s, 1H), 7.28(m, 1H), 6.54 (m, 1H), 2.50 (s, 3H).

Preparation 7 (5-hydroxybenzofur-7-yl)acetonitrile

Dissolve [5-(tetrahydropyran-2-yloxy)benzofur-7-yl]acetonitrile (3.89 g,0.015 mol) in methanol (100 mL) and add para-toluene sulfonic acidmonohydrate (0.288 g, 0.1 equivalent). After 20 minutes extract withethyl acetate against water, then wash with brine. Concentration invacuo affords 2.5 g (95.5%) of the title compound as an off-white solid.HRMS(m/z): Calcd 173.0465 Found 173.0477.

Preparation 8 5-Bromoimidazo[1,2-a]pyridine

Add 2-bromo-1,1-diethoxyethane (3.64 g, 18.48 mmol) to a solution of6-bromopyridin-2-ylamine (1.0 g, 5.77 mmol) in n-butanol (40 ml). Refluxovernight and cool. Filtration of the reaction mixture gives 1.3 g (81%)of 5-bromoimidazo[1,2-a]pyridine hydrobromide as a white solid. ESMS(M++1): 198.9 m/z.

Add saturated sodium bicarbonate (300 ml) to a suspension of5-bromoimidazo[1,2-a]pyridine hydrobromide (13.0 g, 46.96 mmol) in ethylacetate. Separate the organic layer, wash with saturated sodiumbicarbonate, dry over magnesium sulfate, and concentrate under reducedpressure to give 9.7 g (100%) of the title compound as a white solid.

Preparation 92-{4-[2-(Tetrahydropyran-2-yloxy)ethoxy]benzofur-7-yl}acetamide a)7-Bromo-4-[2-(tetrahydropyran-2-yloxy)ethoxy]benzofuran

Potassium carbonate (6.399 g, 46.299 mmol) is added to a solution of7-bromobenzofur-4-ol (3.266 g, 15.331 mmol) in DMF (30 ml) undernitrogen. 2-(2-bromoethoxy)tetrahydropyran (2.22 mL, 18.386 mmol) isintroduced and refluxed at 80° C. for 16 hours. The mixture is dilutedwith ethyl acetate, washed with water and brine, dried over sodiumsulfate, filtered, and concentrated. Purification by flashchromatography and eluting with hexane: ethyl acetate gives 3.538 g(68%) of the title compound as an oil. MS(ES)(m/z) 211 (M+−1-129), 255(M⁺−1-85).

b) {4-[2-(Tetrahydropyran-2-yloxy)ethoxy]benzofur-7-yl}acetic acid ethylester

Combine 7-Bromo-4-[2-(tetrahydropyran-2-yloxy)ethoxy]benzofuran (2.598g, 7.61 mmol), bis(dibenzylideneacetone) palladium (0.461 g, 0.802mmol), and 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl (0.308g, 0.783 mmol) in tetrahydrofuran (15 ml) under nitrogen. Addbromo(2-ethoxy-2-oxoethyl)zinc (2 equiv.), and heat the mixture at 80°C. for 16 hours. (Knochel, P.; Honed, P.; Eds. Organozinc Reagents: APractical Approach; Oxford University Press, Inc: London, 1999). Coolthe mixture to room temperature, filter through a silica plug elutingwith ethyl ether, and concentrate. Purify by flash chromatography andelute with hexane:ethyl acetate to give 1.422 g (54%) of the titlecompound as an oil. Mass spectrum: electrospray (m/z) 265 (M⁺+1-85).

c) {4-[2-(Tetrahydropyran-2-yloxy)ethoxy]benzofur-7-yl}acetic acid

Add to a cooled solution (0° C.) of{4-[2-(tetrahydropyran-2-yloxy)ethoxy]-benzofur-7-yl}acetic acid ethylester (1.363 g, 3.912 mmol) in dimethylformamide (20 ml) 2M aqueoussodium hydroxide (10 ml), and stir the mixture for 1½ hours at roomtemperature. Dilute the mixture with ethyl acetate and extract withwater. Dilute with methylene chloride (50 ml) and neutralize using 0.1Maqueous hydrochloric acid (100 ml). Separate the layers are separatedand extract the water layer with methylene chloride. Combine themethylene chloride layers, dry over sodium sulfate, filter, andconcentrate to obtain 0.920 g (68%) of the title compound as an oil.Mass spectrum: electrospray (m/z) 319 (M−1).

d) 2-{4-[2-(Tetrahydropyran-2-yloxy)ethoxy]benzofur-7-yl}acetamide

Combine {4-[2-(Tetrahydropyran-2-yloxy)ethoxy]benzofur-7-yl}acetic acid(0.920 g, 2.872 mmol), and 1,1-carbonyldiimidazole (2.365 g, 14.585mmol) in tetrahydrofuran (15 ml), and stir for 1 hour under nitrogen.Cool the mixture to 0° C., and add concentrated aqueous ammoniumhydroxide (2 ml). Remove the ice bath, and stir the mixture at roomtemperature for 16 hours. Dilute the mixture with ethyl acetate, washwith water and brine, dry over sodium sulfate, filter, and concentrate.Purification using flash chromatography and eluting with hexane:ethylacetate gives 0.732 g (80%) of the title product as a white solid. Massspectrum: electrospray (m/z) 236 (M⁺+1-85).

Preparation 10 2-(Benzofur-4-yl)acetamide

Add 1,1′-carbonyldiimidazole (2.3 g, 14.2 mmol) to a solution ofbenzofur-4-ylacetic acid (2.5 g, 14.2 mmol) in anhydrous tetrahydrofuran(12 mL) under nitrogen and stir at 20° C. for 4 hours. Bubble anhydrousammonia through the solution, dilute with anhydrous tetrahydrofuran (10mL), and stir at 20° C. for 18 hours. Concentrate under reducedpressure, and wash the solid with aqueous sodium hydrogen sulfate anddistilled water. Dry under vacuum to obtain 2.3 g (93%) of the titlecompound as a pale yellow solid. Mass spectrum (ES, m/z) (M+H)=176.1.

Preparation 11 N-(7-Cyanomethylbenzofur-4-yl)acetamide a)2-(2,2-Dimethoxyethoxy)-1-methyl-4-nitrobenzene

Add bromoacetaldehyde dimethylacetal (30.3 g, 179 mmol) to2-methyl-5-nitrophenol (25 g, 163 mmol) and potassium carbonate (50 g,362 mmol) in dimethylformamide (200 mL). Stir the mixture and refluxunder nitrogen for 2.5 hours. Cool the mixture to 20° C. and add aqueoussodium hydroxide (200 mL, 1 M). Dilute the mixture with hexane anddiethyl ether (1:1), then wash with 0.2M aqueous sodium hydroxide andaqueous saturated sodium chloride. Dry over anhydrous magnesium sulfate,filter, and concentrate under reduced pressure. Precipitation of theproduct from hexane gives 30.6 g (77%) of the title compound, as a tancolored solid. ¹H NMR (400 MHz, CDCl₃) δ 7.78 (dd, 1H, J=8.4, 2.4 Hz),7.66 (d, 1H, J=2.4 Hz), 7.26 (dd, 1H, J=8.4, 0.8 Hz), 4.76 (t, 1H, J=4.8Hz), 4.09 (d, 2H, J=35.2 Hz), 3.48 (s, 6H), 2.32 (s, 3H).

b) 7-Methyl-4-nitrobenzofuran

Add Amberlyst® 15 ion-exchange resin (36 g) to chlorobenzene (700 mL),and heat the mixture to reflux and azeotrope out water, to dry theresin. Dissolve 2-(2,2-dimethoxyethoxy)-1-methyl-4-nitrobenzene (34.8 g,144 mmol) in chlorobenzene (125 mL), and add this mixture dropwise tothe stirring, refluxing reaction mixture under nitrogen over a 15 minuteperiod. Continue refluxing for 1.5 hours, then cool to room temperature.Filter to remove the resin and concentrate under reduced pressure.Dissolve the residue in hexane and diethyl ether (1:1), then wash with0.5M aqueous sodium hydroxide and aqueous saturated sodium chloride. Dryover anhydrous magnesium sulfate, filter, and concentrate under reducedpressure. Chromatography on flash silica using hexane and ethyl acetate(9:1) and precipitation from hexane and toluene (1:1) yielded 9.7 g(42%) of the title compound as a yellow solid (42%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.36 (d, 1H, J=2.0 Hz), 8.12 (d, 1H, J=8.4 Hz), 7.44 (d, 1H,J=2.4 Hz), 7.38 (d, 1H, J=8.8 Hz), 2.59 (s, 3H).

c) Dimethyl[2-(4-nitrobenzofur-7-yl)vinyl]amine

Add 7-methyl-4-nitrobenzofuran (3.5 g, 19.7 mmol) totert-butoxybis(dimethylamino)methane (10.3 g, 59.1 mmol), and reflux themixture under nitrogen for 40 minutes. Concentrate under reducedpressure, dissolve in xylenes (50 mL), concentrate under reducedpressure, and dry under vacuum to obtain 4.9 g (100%) of the titlecompound as a deep red-brown solid.

HRMS (M+H)=233.0928.

d) (4-Nitrobenzofur-7-yl)acetonitrile

Add dimethyl[2-(4-nitrobenzofur-7-yl)vinyl]amine (4.8 g, 20.6 mmol) andhydroxylamine-O-sulfonic acid (4.6 g, 40.6 mmol) to dimethylformamide(45 mL) and stir at room temperature for 15 minutes. Heat at 100° C.under nitrogen for 1 hour, cool to room temperature, dilute with diethylether, and wash with water and aqueous saturated sodium chloride. Dryover anhydrous magnesium sulfate, filter, and concentrate under reducedpressure. Chromatography on flash silica using 85% hexane, 15% ethylacetate gives 2.9 g (64%) of the title compound as a light brown solid.Mass spectrum (ES, m/z) (M−1)=200.9.

d) N-(7-Cyanomethylbenzofur-4-yl)acetamide

Add (4-nitrobenzofur-7-yl)acetonitrile (600 mg, 2.96 mmol), aceticanhydride (600 mg, 5.88 mmol), and 5% palladium on carbon (300 mg) totetrahydrofuran (25 mL). Stir under hydrogen (1 atm) for 45 minutes.Dilute with ethyl acetate, filter through a pad of Celite®, andconcentrate under reduced pressure. Chromatograph on flash silica using75% ethyl acetate, 25% hexane gives 430 mg (67%) of the title compoundas an off-white solid. HRMS (M+H)=215.0816.

Oxoacetic Acid Formation:

Preparation 12{5-[3-(tert-Butyldimethylsilyloxy)propoxy]-1-isopropyl-1H-indol-3-yl}oxoaceticacid methyl ester

Dissolve5-[3-(tert-butyldimethyl-silyloxy)propoxy]-1-isopropyl-1H-indole (0.43g, 1.124 mmol) in tetrahydrofuran (40 mL). Add 2,6-lutidine (0.43 mL, 3eq) and cool to 0° C. Add oxalyl chloride dropwise and stir for 1.5hours then cool to −78° C., add methanol (0.1 mL, 2 eq) and treated withsodium methoxide (25% w/w in methanol, 22.5 mL). Stir for 1 hour thendilute with ethyl acetate and extract with saturated sodium bicarbanatethen brine. Dry over magnesium sulfate, filter and concentrate.Purification by column chromatography (4:1 hexanes:ethyl acetate)affords the title compound as a light yellow oil. MS (ES, m/z): 434.3(M+1).

The following compounds are prepared in a similar manner: PREP. #Product Physical Data 13 {7-[3-(tert-Butyldimethyl-silyloxy)propyl]-1-MS(ES, m/z): isopropyl-1H-indol-3-yl}oxoacetic acid (M+1) 418.2 methylester 14 (2-cyclopropyl-1H-indol-3-yl)oxoacetic acid MS(ES, m/z): methylester (M+1) 244.0 15 (2-isopropyl-1H-indol-3-yl)oxoacetic acid MS(ES,m/z): methyl ester (M+1) 246 16 [N-(endo-8-Carbethoxy- MS(ES, m/z):azabicyclo[3.2.1]octan-3-yl)-indol-3- (M+1) 384 yl]oxoacetic acid methylester 17 [1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-4-fluoro- ¹H NMR(DMSO-1H-indol-3-yl]oxoacetic acid methyl ester d6) δ 8.44(s, 1H), 7.62(d,J=8.07Hz, 1H), 7.33(m, 1H), 7.06(m, 1H), 4.64(m, 1H), 3.94˜3.88(m, 4H),3.87(s, 3H), 2.00(m, 4H), 1.80(m, 4H) 18[1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-1H-indol- MS(ES, m/z): 3-yl]oxoaceticacid methyl ester 344.17(M⁺+1) 19[5-(2-tert-butoxyethoxy)-N-methylindol-3- MS(ES, m/z): yl]oxoacetic acidmethyl ester 278(M⁺+1-56). 20 4-(3-Methoxyoxalylindol-1-yl)-2- MS(ES,m/z): methylpiperidine-1-carboxylic acid tert-butyl (M+1) 401.2 ester 21Cis 4-(3-Methoxyoxalyl-indol-1-yl)-3- ES(M+1): 401.2methylpiperidine-1-carboxylic acid tert-butyl ester 22(Imidazo[1,2-a]pyridin-3-yl)oxoacetic acid ESMS(M⁺+1): methyl ester204.9 m/z.

Preparation 23 (5-fluorobenzofur-7-yl)oxoacetic acid ethyl ester

Dissolve 7-bromo-5-fluorobenzofuran (2 g, 9.3 mmol) in 5 mltetrahydrofuran under nitrogen. Add magnesium turnings (0.25 g, 1.1equivalents) and heat to reflux to facilitate Grignard formation. In aseparate flask place diethyl oxalate (1.3 mL, 2 equivalents) in 3 mLtetrahydrofuran, and cool to 0° C. under nitrogen. When Grignardformulation is complete, add via canula to the diethyl oxalate solution.Stir the reaction for 2-4 hours while slowly warming to 20° C. Extractwith diethyl ether. Wash organic layer with brine. Dry over magnesiumsulfate, filter and concentrate to a light yellow oil. Purifacation bycolumn chromatography (4:1 hexanes:ethyl acetate) affords 1.74 g (79%)of an oil which solidifies upon standing. MS (ES, m/z): 237.0 (M+1).

The following compounds may be prepared in a similar manner: PREP. #Product Physical Data 24 (Benzofur-7-yl)oxoacetic acid methyl esterES(M+1) 218.9 25 (4-Methoxybenzofur-7-yl)-oxoacetic acid ES(M+1) 248.9ethyl ester 26 (5-Methoxybenzofur-7-yl)-oxoacetic acid ES(M+1) 249.0ethyl ester 27 (6-Methoxybenzofur-7-yl)-oxoacetic acid 1H NMR(400MHz,ethyl ester CDCl3) δ 1.41(t, J=7.31Hz, 3H), 4.40(m, 2H), 6.74(d,J=1.95Hz, 1H), 6.94(d, J=8.78Hz, 1H), 7.68(d, J=2.44Hz, 1H), 7.78(d,J=8.23Hz, 1H) 28 (Benzofur-7-yl)oxoacetic acid methyl ester ES(M+1)218.9 29 (4-Methoxybenzofur-7-yl)oxoacetic acid ES(M+1) 248.9 ethylester 30 (5-Methoxybenzofur-7-yl)oxoacetic acid ES(M +1) 249.0 ethylester 31 (6-Methoxybenzofur-7-yl)oxoacetic acid 1H NMR(400MHz, ethylester CDCl3) δ 1.41(t, J=7.31Hz, 3H), 4.40(m, 2H), 6.74(d, J=1.95Hz,1H), 6.94(d, J=8.78Hz, 1H), 7.68(d, J=2.44Hz, 1H), 7.78(d, J=8.23Hz, 1H)32 Imidazo[1,2-a]pyridin-5-yloxoacetic acid ethyl ester

Preparation 33{1-[3-(tert-Butyldimethyl-silyloxy)propyl]-1H-indol-4-yl}-oxoacetic acidmethyl ester

Add tert-butyl lithium (88.1 ml, 149.8 mmol, 1.7 M in hexane) to asolution of 4-Bromo-1-[3-(tert-butyldimethyl-silyloxy)propyl]-1H-indole(22.0 g, 59.92 mmol) in anhydrous tetrahydrofuran (100 ml) at −78° C.Stir the reaction at −78° C. for 20 min. Transfer the mixture into asolution of dimethyl oxalate (24.8 g, 209.72 mmol) in tetrahydrofuran(400 ml) at −40° C. via a dry-ice cooled cannula. Upon completeaddition, stir the reaction at −78° C. for 15 minutes and slowly warm toroom temperature. Quench the reaction with saturated aqueous ammoniumchloride and extract into ethyl acetate. Combine the organic layers, dryover magnesium sulfate, and concentrate under reduced pressure.Purification by flash chromatography and eluting with ethylacetate:hexane gradient (100% hexane to 15% ethyl acetate:hexane over 90minutes) gives the title compound (16.89 g, 75%), as a light brown oil.ESMS (M⁺+1): 376.2 m/z.

Using a similar method as above the following compounds may be preparedand isolated: PREP. # Product Physical Data 34(1-Methyl-1H-indol-4-yl)oxoacetic acid HRMS(M+H): methyl ester 218.082635 {1-[2-(tert-Butyl-dimethyl-silyloxy)-ethyl]- ESMS(M⁺+1)6-methoxy-1H-indol-3-yl}oxoacetic acid 392.1 m/z. methyl ester 36(Benzofur-7-yl)oxoacetic acid methyl ester HRMS(M+H): 205.0501 374-(Methoxybenzofur-7-yl)oxoacetic acid HRMS(M+Na): ethyl ester 271.057038 5-(Methoxybenzofur-7-yl)oxoacetic acid ES(m/ ethyl esterz)(M+1)=249.0 39 (5-Benzyloxybenzofur-7-yl)oxoacetic acid HRMS(ES+):methyl ester 325.12

Preparation 40 (Isoquinolin-5-yl)oxoacetic acid methyl ester

5-Aminoisoquinoline (20 g, 139 mmol) is dissolved in hydrobromic acid(48%, 100 mL) in a 500 ml round bottom flask, and then a solution ofsodium nitrite (9.6 g, 139 mmol) in water (50 mL) added cautiously at 0°C. The white slurry turns bright red upon complete addition of the salt,and then this solution is transferred to another 500 mL vesselcontaining CuBr (25 g, 174 mmol) stirring in hydrobromic acid (48%, 200mL) at 75° C. This transfer is performed slowly and carefully. Aftercomplete addition, the mixture is allowed to stir at 75° C. for onehour, then cooled to room temperature, and kept stirring overnight. Themixture is then placed onto an ice bath and some ice added to thesolution, then basified using sodium hydroxide aqueous solution (20%,250 mL) solution. Then slurry is filtered and then filtrate is extractedwith diethyl ether. The solid and the extract are then combined andsonicated for one hour in chloroform. This sludge is filtered through aplug of Celite, and the chloroform removed by rotovap. The finalcompound is obtained in pure form by column chromatography in chloroformwith 36% yield, 10.4 g (50 mmol) of 5-Bromo-isoquinoline. MS (ES, m/z):208.0 (M⁺(⁷⁹Br)+1), 210.0 (M⁺(⁸¹Br)+1).

Tert-BuLi (1.7 M pentane, 27.2 mL, 46.3 mmol) is added to dry THF (195mL) at −78° C., after few minutes, a solution of 5-bromo-isoquinoline(6.42 g, 30.86 mmol) in THF (5 mL) is added via syringe dropwise. Theresulting solution is allowed to stir at −78° C. for 45 minutes, thendimethyl oxalate (11 g, 93 mmol) is added in one portion. After 30 minat −78° C., the reaction is quenched using saturated ammonium chloridesolution, diluted with 200 mL EtOAc, and then the TB is removed byrotovap. The residue is diluted with saturated ammonium chloridesolution extracted with EtOAc (2×200 mL). The organic layers arecombined and washed with 1×75 mL water and 1×75 mL brine, dried overanhydrous sodium sulfate, then concentrated. The material is thenpurified using flash column chromatography, 20% EtOAC/Hexanes, to yield3.91 g, 59% of isoquinolin-5-yloxoacetic acid methyl ester. MS (ES,m/z): (M⁺30 1) 216.1

Preparation 42 (5-Methoxybenzofur-7-yl)acetic acid ethyl ester

Dissolve 7-bromo-5-methoxybenzofuran (6.0 g, 26.43 mmol),bis(dibenzylideneacetone)palladium (1.32 g, 2.3 mmol) and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (2.7 g, 6.86mmol) in anhydrous tetrahydrofuran (36 mL), add freshly prepared2-ethoxy-2-oxoethylzinc bromide in tetrahydrofuran (66 mL). Heat at50-60° C. for 5 h. Cool and filter mixture through celite and evaporateto a thick red-brown oil (30 g). Purify by flash chromatography using agradient of ethyl acetate in hexanes yields the pure compound as a thickyellow oil (6.2 g, quant). ESMS m/z (relative intensity) 235.2 (M++H+,10), 161.1 (M+−CO2Et+H+, 100).

Acetamide Formation:

Preparation 43 4,5-Difluorobenzofur-7-carboxaldehyde

Dissolve 7-Bromo-4,5-difluorobenzofuran (5.0 g, 23.5 mmol) in anhydroustetrahydrofuran (15 mL) under nitrogen and add magnesium metal turnings(712 mg, 29.3 mmol). Stir and warm the reaction to 50° C. to initiatethe Grignard reagent formation. After the exothermic reaction subsides,reflux for 30 minutes. Dilute the solution with tetrahydrofuran (15 ml)and cool to 25° C. Add the Grignard reagent dropwise via cannula to astirring solution of N,N-dimethylformamide (10.2 g, 139 mmol) intetrahydrofuran (25 mL) at −78° C. under nitrogen. Stir the reaction at0° C. for 1 hour and quench with aqueous saturated ammonium chloride.Dilute with diethyl ether, wash with distilled water, and aqueoussaturated sodium chloride. Dry the organic phase over anhydrousmagnesium sulfate, filter, and concentrate under reduced pressure.Chromatograph on flash silica using a gradient from neat hexane to 50%ethyl acetate in hexane to obtain 2.65 g (69%) of the title compound asan off-white solid. HRMS (M+)=182.0179.

Using similar procedures the following aldehydes may be prepared andisolated: PREP. # Product Physical Data 44 (4-Methoxybenzofur-7- 1HNMR(400MHz, DMSO- yl)carboxaldehyde d_(d))10.1(s, 1H), 8.06(s, 1H),7.85(d, J=9Hz, 1H), 7.04(m, 2H, 4.0(s, 2H) 45 (5-Methoxybenzofur-7-yl)carboxaldehyde 46 (4-Fluorobenzofur-7- 1H NMR(400MHz, DMSO-d_(d))yl)carboxaldehyde 10.21(s, 1H), 8.21(d, J=2Hz, 1H), 7.89(dd, J=8, 8Hz,1H), 7.28(dd, J=8, 8Hz, 1H), 7.2(d, J=2Hz, 1H) 47 Benzofur-7-HRMS(M)=146.0364 carboxaldehyde 48 5-[(tetrahydropyran-2- MS(ES, m/z):246.9(M+1). yloxy)benzofur-7- yl]carboxaldehyde

Preparation 491-[3-(tert-Butyldimethylsilyloxy)propyl]-1H-indole-4-carboxaldehyde

Add tert-butyl lithium (27.07 ml, 46.03 mmol, 1.7 M in pentane) to asolution of 4-Bromo-1-[3-(tert-butyldimethylsilyloxy)propyl]-1H-indole(6.76 g, 18.41 mmol) in anhydrous tetrahydrofuran (100 ml) at −78° C.Stir the reaction at −78° C. for 30 min, quench withN,N-dimethylformamide (4.7 ml, 64.45 mmol), warm to 0° C., quench withpH7 buffer, and extract into ethyl acetate. Combine the organic layers,dry over magnesium sulfate, and concentrate under reduced pressure.Purification by flash chromatography and eluting with ethylacetate:hexane gradient (100% hexane to 50% ethyl acetate:hexane over 45minutes) gives the title compound, (4.81 g, 82%) as a clear oil. ESMS(M++1): 318.2 m/z.

Using similar procedures the following aldehydes may be prepared andisolated: PREP. # Product Physical Data 50 1-[3-(tert- ESMS(M++1):Butyldimethylsilyloxy)propyl]-1H- 318.2 m/z indole-4-carboxaldehyde 511-Methyl-1H-indole-4- HRMS(M+H)=160.0760 carboxaldehyde 52(4,5-Difluorobenzofur-7- HRMS(M+)=182.0179. yl)carboxaldehyde 53(5-Fluorobenzofur-7- 1H NMR(400MHz, yl)carboxaldehyde DMSO-dd) 10.25(s,1H), 8.25(d, J=2Hz, 1H), 7.87(dd, J=8, 3Hz), 7.65(J=8, 3Hz), 7.1(d, J=2,1H). 54 (5,6-Difluorobenzofur-7- HRMS(M+) yl)carboxaldehyde 182.0179 55(6-Fluorobenzofur-7- ESMS(M++) 165.0 yl)carboxaldehyde

Preparation 56{1-[3-(tert-Butyldimethylsilyloxy)propyl]-1H-indol-4-yl}acetonitrile

Add 1-[3-(tert-Butyldimethylsilyloxy)propyl]-1H-indole-4-carboxaldehyde(2.34 g, 14.4 mmol) and lithium cyanide tetrahydrofuran complex(LiCN*1.5 THF, 204 mg, 1.44 mmol) to tetrahydrofuran (40 mL) undernitrogen. Add dropwise neat diethyl cyanophosphonate (2.8 mL, 18.4 mmol)to the stirring reaction mixture. Stir at room temp under nitrogen for60 hours. Add 2-methyl-2-propanol (1.4 mL, 14.6 mmol). Add the reactionmixture via cannula to a stirred 0.1 molar solution of samarium(II)iodide in tetrahydrofuran (360 mL, 36.0 mmol) at 25° C. under nitrogen.If the resulting reaction mixture is not deep blue add additionalsamarium(II) iodide solution until deep blue color persists. Stir thereaction at 25° C. for 1 hour. Concentrate under reduced pressure,dilute with ethyl acetate, diethyl ether (1:1), wash with aqueous 0.1molar hydrochloric acid, and aqueous saturated sodium chloride. Dry theorganic phase over anhydrous magnesium sulfate, filter, and concentrateunder reduced pressure. Chromatograph on flash silica using a gradientfrom neat hexane to 25% ethyl acetate in hexane to obtain 2.1 g (84%) ofthe title compound as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) 7.43(d, J=8 Hz, 1H), 7.38 (m, 1H), 7.14 (m, 1H), 7.0 (d, J=8 Hz, 1H), 6.54(m, 1H), 4.23 (t, J=7, 2H), 4.18 (s, 3H), 3.5 (t, J=7 z, 2H), 1.9 (m,2H), 0.85 (s, 9H), 0.0 (s, 6H).

Using similar method as above the following nitriles may be prepared andisolated: PREP. # Product Physical Data 57 (1-Methyl-1H-indol-4-HRMS(M+H)=171.0939 yl)acetonitrile 58 (1H-Indol-7-yl)acetonitrileHRMS(M+)=156.0687 59 (4-Methoxybenzofur-7-yl)acetonitrile 1H NMR(400MHz,DMSO-d_(d)) 7.99(d, J=2Hz, 1H), 7.23(d, J=8Hz, 1H), 6.98(d, J=2Hz, 1H)6.8(d, J=8Hz, 1H), 4.16(s, 2H), 3.88(s, 3H) 60(5-Methoxybenzofur-7-yl)acetonitrile 1H NMR(400MHz, DMSO-d_(d)) 8.02(d,J=2.2Hz, 1H), 7.17(d, J=2.2Hz, 1H), 6.9(m, 2H), 4.24(s, 3H) 61(4-Fluorobenzofur-7-yl)acetonitrile 1H NMR(400MHz, DMSO-d_(d)) 8.15(d,J=2.2Hz, 1H), 7.33(m, 1H), 7.17-7.1(m, 2H), 4.26(s, 2H) 62(4,5-Difluorobenzofur-7- 1H NMR(400MHz, yl)acetonitrile DMSO-d_(d))8.2(d, J<1Hz, 1H), 7.42(m, 1H), 7.22(d, J<1Hz, 1H), 4.28(s, 2H)(carriedfurther without purification) 63 (5-Fluorobenzofur-7-yl)acetonitrile 1HNMR(400MHz, DMSO-d_(d)) 8.15(d, J=2Hz, 1H), 7.47(dd, J=8, 2Hz, 1H),7.18(dd, J=8, 2Hz, 1H), 7.01(d, J=2Hz, 1H), 4.3(s, 2H) 64(5,6-Difluorobenzofur-7- ESMS(M⁻−1): 192.3 yl)acetonitrile 65(6-Fluorobenzofur-7-yl)acetonitrile 1H NMR(400MHz, CDCl₃-d6) 7.62(d,J=2.44Hz, 1H), 7.47(m, 1H), 7.00(m, 1H), 6.72(d, J=2.44Hz, 1H), 3.91(s,2H) 66 (Benzofur-7-yl)acetonitrile HRMS(M)=157.0524 67[5-(tetrahydro-pyran-2- 1H NMR(400MHz, yloxy)benzofur-7-yl]acetonitrileCDCl3) δ 1.70(m, 6H), 3.54(m, 1H), 3.88(m, 1H), 3.91(s, 2H), 5.34(t,J=3.17Hz, 1H), 6.67(d, J=2.20Hz, 1H), 7.01(d, J=1.95Hz, 1H), 7.20(d,J=2.44Hz, 1H), 7.55(d, J=2.20Hz, 1H).

Preparation 682-{1-[3-(tert-Butyldimethylsilyloxy)propyl]-1H-indol-4-yl}acetamide

Add {1-[3-(tert-Butyldimethylsilyloxy)propyl]-1H-indol-4-yl}acetonitrile(1.9 g, 11.0 mmol) to 2-methyl-2-propanol (20 mL). Heat to reflux undernitrogen and add potassium hydroxide pellets (7.4 g, 132 mmol). Stir andreflux under nitrogen for 30 minutes. Pour solution off of the excesspotassium hydroxide and dilute with ethyl acetate. Wash with a 1:1mixture of aqueous saturated sodium chloride, aqueous saturated sodiumhydrogen carbonate. Dry the organic phase over anhydrous magnesiumsulfate, filter, and concentrate under reduced pressure. Rinse the solidwith cold diethyl ether and dry under vacuum to obtain 1.62 g (77%) ofthe title compound as an off-white solid. ESMS (M⁺+1): 347.2.

Using similar methods as above the following acetamides are prepared andisolated: PREP. # Product Physical Data 69 2-(1-Methyl-1H-indol-4-HRMS(M+H)=189.1028 yl)acetamide 70 2-(1H-Indol-7-yl)acetamide 1HNMR(400MHz, DMSO-d_(d)) 10.9(bs, 1H), 7.44-7.37(m, 2H), 7.32(dd, J=2,<1), 6.98-6.91(m 3H), 6.41(m, 1H), 3.62(s, 2H) 712-(4-Methoxybenzofur-7- ESMS(M⁺+1) 206.0 yl)acetamide 722-(5-Methoxybenzofur-7- 1H NMR(400MHz, DMSO-d_(d)) yl)acetamide 7.91(d,J=2Hz, 1H), 7.5(bs, 1H), 7.1(d, J=2Hz, 1H), 6.96(bs, 1H), 6.85(d, J=2HZ,1H) 6.8(d, J=2Hz, 1H), 3.74(s, 3H), 3.61(s, 2H) 732-(4-Fluorobenzofur-7- HRMS(M+1)=194.0617 yl)acetamide 742-(4,5-Difluorobenzofur-7- 1H NMR(400MHz, DMSO-d_(d)) yl)acetamide8.1(d, J=2Hz, 1H), 7.55(bs, 1H), 7.27(m, 2H), 7.14(d, J=2Hz, 1H),7.01(bs, 1H), 3.65(s, 2H) 75 2-(5-Fluorobenzofur-7- ESMS(M⁺+1): 194.1yl)acetamide 76 2-(5,6-Difluorobenzofur-7- 1H NMR(400MHZ, DMSO-d_(d))yl)acetamide 8.08(d, J=2.2, 1H), 7.63(bs, 1H), 7.59(dd, J=8, 8Hz, 2H),7.09(bs, 1H), 6.9(d, J=2.2Hz, d), 3.75(s, 3H). 77 2-(6-Fluorobenzofur-7-ESMS(M⁺+1): 194.0 yl)acetamide 78 2-(Benzofur-7-yl)acetamideHRMS(M+H)=176.0717 79 2-(Furo[3,2-c]pyridin-7- ESMS: (M++1):yl)acetamide 177.1 m/z. 80 2-(4-Acetylaminobenzofur-7-HRMS(M+H)=255.0733 yl)acetamide 81 2-[5-(1-benzylpiperidin-4- MS(ES,m/z): 365.1(M+1) yloxy)benzofur-7- yl]acetamide 821-(3-Hydroxypropyl)indole-3- HRMS(M+H)=233.1291. acetamide 831-(tert-butoxycarbonyl)-4-(7- MS(ES, m/z): 275.1(productcarbamoyl-methylbenzofur-5- minus Boc), (M+1) yloxy)piperidine

Preparation 84 2-(8-Hydroxymethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol10-yl)acetamide

Dissolve the indole (3.54 mmol) and N,N,-dimethylmethyleneammoniumchloride (0.372 g, 4.00 mmol) in dichloromethane (15 mL), stir themixture is at room temperature for 24˜72 h. under nitrogen. Wash withwater (5 mL), follow by addition of base to neutralize the acid (3.6 mL,1M NaOH). Extract with ethyl acetate (2×100 mL), wash with saturatedNaCl, then dry over anhydrous magnesium sulfate. Remove the solvent invacuo to give (1H-Indol-3-ylmethyl)-dimethyl-amine.

Dissolve a mixture of the (1H-Indol-3-ylmethyl)-dimethylamine (3.54mmol), sodium cyanide (0.500 g, 10.62 mmol), and ethyl acetate (1.7 mL,17.7 mmol) in dry dimethyl sulfoxide (12 mL) and heat to 80° C. undernitrogen for 3 h. Cool the reaction mixture to room temperature, dilutewith ethyl acetate (150 mL), and wash with water (50 mL), Dry theorganic layer over anhydrous magnesium sulfate, and remove the solventin vacuo to yield (1H-indol-3-yl)-acetonitrile 0.850 g (96%).

Dissolve (1H-indol-3-yl)acetonitrile (3.40 mmol) in dry dimethylsulfoxide (3.0 mL), cool in an ice bath, combine with anhydrouspotassium carbonate (0.200 g) and 30% hydrogen peroxide (0.6 mL),keeping the reaction temperature below 20° C. Warm to room temperature,add water (10 mL) and filter the resulting solid, dry under vacuum.

MS (ES, m/z): 257.3(M+−1).

Preparation 85 2-(Imidazo[1,2-a]pyridin-3-yl)acetamide a)Imidazo[1,2-a]pyridin-3-ylacetic acid ethyl ester

Add ethyl(E)oxybutenoate (14.3 g, 111.66 mmol) to 2-amino pyridine (10.0g, 106.4 mmol) in acetonitrile (270 ml). Heat the reaction at 80° C. for6 hours. Concentrate the reaction mixture under reduced pressure.Purification of the resulting oil by flash chromatography and elutingwith a gradient from 100% hexane to 95% ethyl acetate:methanol gives thetitle compound, Imidazo[1,2-a]pyridin-3-ylacetic acid ethyl ester (10.95g, 50.0%—determined by NMR) and 2-aminopyridine (co-elution), as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆) 83 (m, 1H), 7.53 (m, 1H), 7.46 (s, 1H),6.9 (m, 1H), 6.42 (m, 1H), 4.1 (q, J=7 Hz, 211), 1.15 (t, J=7 Hz, 3H).

b) 2-(Imidazo[1,2-a]pyridin-3-yl)acetamide

Bubble ammonia through a solution of (Imidazo[1,2-a]pyridin-3-yl)aceticacid ethyl ester (10.0 g, 48.96 mmol) in methanol (30 ml) at 0° C. Heatthe reaction mixture in a sealed tube at 100° C. for 2 hours.Concentrate the reaction mixture under reduced pressure. Tituration inethyl acetate to gives the title compound (5.0 g, 58.2%), as a whitesolid. ESMS (M⁺+1): 176.1 m/z.

Preparation 86(R)-2-[5-(1-Benzylpyrrolidin-3-yloxy)benzofur-7-yl]acetamidea)(R)-2-[5-(1-Benzylpyrrolidin-3-yloxy)benzofur-7-yl]acetamide

Add to dry ammonium chloride (0.26 g, 4.87 mmol) in anhydrous toluene (3mL) at −5 to −10° C. a solution of 2.0 M trimethylaluminum in toluene(2.4 mL) and allow the mixture to warm to ambient temperature. When thereaction mixture becomes clear, add(R)-[5-(1-Benzylpyrrolidin-3-yloxy)benzofur-7-yl]acetic acid ethyl ester(0.51 g, 1.34 mmol) in toluene (6 mL) and heat to 50° C. for 3 h. Pourthe reaction mixture into a mixture of concentrated hydrochloric acid (1mL) and water (3 mL), made basic with 5 N sodium hydroxide solution andextract with ethyl acetate. Wash the organic extracts with water, brine,dried and evaporate to dryness to yield the product (0.42 g, 90%), whichis used without further purification.

b) 2-[4-(2-Hydroxyethoxy)benzofur-7-yl]acetamide

Add to a solution of2-{4-[2-(tetrahydropyran-2-yloxy]benzofur-7-yl}acetamide (0.216 g, 0.676mmol) in methyl alcohol (7 ml) p-toluenesulfonic acid mono-hydrate(catalytic amount), and stir the mixture for 1 hour. Dilute the mixturewith ethyl acetate, wash with 1N aqueous sodium bicarbonate, water, andbrine, dry over sodium sulfate, filter, and concentrate to give 0.05 g(31%) of the title compound as a off-white solid. Mass Spectrum:electrospray (e/z) 236 (M⁺+1).

Preparation 872-[1-(1-Benzylpiperidin-4-yl)-1H-indol-3-yl]-2-hydroxyacetamide

Dissolve [1-(1-benzylpiperidin-4-yl)-1H-indol-3-yl]oxoacetic acid methylester (1.29 g, 3.43 mmol) in 2 M ammonia: methanol (35 mL) and stir atroom temperature under nitrogen for 1.5 hours. Concentrate to a whitesolid and slurry into absolute ethanol (40 mL). Add sodium borohydride(0.65 g, 5 equiv) and stir 3 hours at room temperature under nitrogen.Concentrate then dilute with ethyl acetate and quench with water. Washorganic layer with brine. Dry over magnesium sulfate, filter andconcentrate to give crude product (1.28 g, 103%). MS (ES, m/z): 364.2(M+1).

Synthetic Transformation of Intermediates:

O-Alkylations:

Preparation 88 5-(2-(tert-butoxy)ethoxy)-1H-indole

Add triphenylphosphine (600 mg, 2.29 mmol) to a solution of diethylazodicarboxylate (0.36 mL, 2.29 mmol) in methylene chloride (10 ml) at0° C. followed by ethylene glycol mono-t-butyl ether (0.30 mL, 2.29mmol), and stir the mixture for 20 minutes at 0° C. Add 5-hydroxyindole(200 mg, 1.5 mmol), remove the cold bath, and stir for 5 hours. Addwater (2 mL), transfer the resultant mixture to a separatory funnel, andseparate the layers. Wash the organic layer with 0.1 N aqueous HCl andbrine, then dry over sodium sulfate, filter, and concentrate.Purification by flash chromatography and eluting with hexane:ethylacetate gives 127 mg (36%) of the title compound as a light yellowsolid. Mass spectrum: electrospray (m/z) 232 (M⁻−1).

Using similar methods as above the following compounds may be preparedand isolated: PREP. # Product Physical Data 894-(1H-Indol-5-yloxymethyl)- MS(ES, m/z): 329.3(M−1).piperidine-1-carboxylic acid tert-butyl ester 904-(7-cyanomethylbenzofur-5- MS(ES, m/z): 301.1(productyloxy)piperidine-1-carboxylic minus t-Bu), 257.0(product acid tert-butylester) minus -Boc)(M+1) 91 [5-(1-benzylpiperidin-4- MS(ES, m/z):347.1(M+1) yloxy)benzofur-7- yl]acetonitrile 92(R)-[5-(1-Benzylpyrrolidin-3- ESMS m/z(relative intensity)yloxy)benzofur-7-yl]acetic 380.2(M++H+, 100) acid ethyl ester

Preparation 934-Bromo-1-[3-(tert-butyldimethylsilyloxy)propyl]-1H-indole

Add sodium hydride (4.89 g, 122.4 mmol, 60% dispersion in mineral oil)to a solution of 4-Bromo-1H-indole (12 g, 61.2 mmol) indimethylformamide (100 ml). Cool the reaction to 0° C. and add(2-bromoethoxy)-tert-butyldimethylsilane (17.04 g, 67.32 mmol). Stir thereaction for 1 hour at room temperature, quench with aqueous saturatedsodium bicarbonate, and extract into ethyl acetate. Combine the organiclayers and wash with saturated aqueous sodium chloride, dry overmagnesium sulfate. Concentrate under reduced pressure to obtain thetitle compound, (22.45 g, 100%), as a clear oil. 1H NMR (400 MHz,DMSO-d6) 7.48 (d, J=8, 1H), 7.4 (d, J=3 Hz, 1H), 7.22 (d, J=8 Hz, 1H),7.05 (dd, J=8, 1 Hz, 1H), 6.4 (d, J=3 Hz, 1H), 4.25 (t, J=7 Hz, 2H),3.49 (t, J=7 Hz, 2H), 1.9 (quintuplet, 2H), 0.82 (s, 9H), 0.0 (s, 6H).

Using the method above, the following compounds may be prepared andisolated. PREP. # Product Physical Data 94 4-Bromo-1-[3-(tert- 1HNMR(400MHz, DMSO-d6) butyldimethyl- 7.48(d, J=8, 1H), 7.4(d, J=3Hz,silyloxy)propyl]-1H-indole 1H), 7.22(d, J=8Hz, 1H), 7.05(dd, J=8, 1Hz,1H), 6.4(d, J=3Hz, 1H), 4.25(t, J=7Hz, 2H), 3.49(t, J=7Hz, 2H),1.9(quintuplet, 2H), 0.82(s, 9H), 0.0(s, 6H) 954-Bromo-1-methyl-1H-indole 1H NMR(400MHz, CDCl3) 7.29-7.25(m, 2H),7.10(d, J=3.2Hz, 1H), 7.07(d, J=8Hz, 1H), 6.53(d, J=2.4Hz, 1H), 3.79(s,3H) 96 1-[2-(tert- HRMS(M⁺+1): 306.1882 Butyldimethylsilyloxy)-ethyl]-6-methoxy-1H-indole 97 5-(2-tert-butoxyethoxy)-N- MS(ES, m/z)248(M⁺+1) methylindole 98 1-(1-Hydroxybutyl)indole-3- MS(FD) m/z(M+1)247(100%). acetamide Anal. Calc'd for C₁₄H₁₈N₂O₂ C, 68.27, H, 7.37, N,11.37. Found 68.29, H, 7.52, N, 11.49. 99 1-(1-Hydroxypropyl)indole-3-HRMS Calcd 233.1290. Found acetamide 233.1291 100 5-[3-(tert- MS(ES,m/z): 306.3(M+1), Butyldimethylsilyloxy)- 304.2(M−1) propoxy]-1H-indole101 5-[4-(tert- Butyldimethylsilyloxy)- butoxy]-1H-indole 1027-[3-(tert- MS(ES, m/z): 292.2(M+1) Butyldimethylsilyloxy)-propyl]-2,3-dihydro-1H-indole 103 7-bromo-5-(tetrahydropyran- ¹HNMR(400MHz, CDCl3) δ 2-yloxy)benzofuran 1.70(m, 6H), 3.57(m, 1H),3.86(m, 1H), 5.31(t, J=3.17Hz, 1H), 6.69(d, J=2.20Hz, 1H), 7.19(m, 2H),7.58(d, J=2.20Hz, 1H) 104 5-Benzyloxy-7- bromobenzofuran 105{4-[3-(tert- Butyldimethylsilyloxy)- propoxy]benzofur-7- yl}acetonitrileAlcohol Conversion to a Bromide:

Preparation 1063-[1-(4-bromobutyl)-1H-indol-3-yl]-4-(4-methoxybenzofur-7-yl)pyrrole-2,5-dione

Dissolve3-[1-(4-hydroxybutyl)-1H-indol-3-yl]-4-(4-methoxybenzofur-7-yl)pyrrole-2,5-dione(0.1 g, 0.232 mmol) in 10 mL dichloromethane. Add carbon tetrabromide(0.077 g, 1 equivalent) and triphenyl phosphine (0.061 g, 1 equivalent).Stir for 10 min, add another equivalent of both reagents. Stir 10 minthen dilute with dichloromethane and wash with water followed by brine.Dry over magnesium sulfate then filter and concentrate. Purification bycolumn chromatography (2% methanol:dichloromethane) affords the titlecompound. MS (ES, m/z): 493.0 (M−1).

The following compounds are prepared in a similar manner: PREP. Physical# Product Data 107 3-[4-(3-Bromopropoxy)benzofur-7-yl]-4-(5,6- ES(M+1)dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrrole- 505.1 2,5-dione 1083-(Benzofur-7-yl)-4-[7-(3-bromopropyl)-1H-indol-3- ES(M+1)yl]pyrrole-2,5-dione 451.1 1093-(Benzofur-7-yl)-4-[7-(3-bromopropyl)-1-methyl- ES(M+1)1H-indol-3-yl]pyrrole-2,5-dione 463.1 1103-(4-Methoxybenzofur-7-yl)-4-[1-(4-bromobutyl)- ES(M−1)1H-indol-3-yl]pyrrole-2,5-dione 493.0 1113-(5-Methoxybenzofur-7-yl)-4-[1-(3-bromopropyl)-1H-indol-3-yl]pyrrole-2,5-dione 1123-(5-Methoxybenzofur-7-yl)-4-[1-(2-bromoethyl)- ES(M−1)1H-indol-3-yl]pyrrole-2,5-dione 464.9 1133-(Benzofur-7-yl)-4-[5-(3-bromopropoxy)-1- ES(M+1)isopropyl-1H-indol-3-yl]pyrrole-2,5-dione 509.0 1143-(Benzofur-7-yl)-4-[7-(3-bromopropyl)-1- ES(M+1)isopropyl-1H-indol-3-yl]pyrrole-2,5-dione 493.1 1153-(Benzofur-7-yl)-4-[5-(4-bromobutoxy)-1- ES(M+1)isopropyl-1H-indol-3-yl]pyrrole-2,5-dione 523.1 1163-(5-Fluorobenzofur-7-yl)-4-[5-(4-bromobutoxy)-1- ES(M+1)isopropyl-1H-indol-3-yl]pyrrole-2,5-dione 541.1 1173-(5,6-Difluorobenzofur-7-yl)-4-[5-(4- ES(M+1)bromobutoxy)-1-isopropyl-1H-indol-3- 559.1 yl]pyrrole-2,5-dione 1183-(6-fluorobenzofur-7-yl)-4-[5-(4-bromobutoxy)-1- ES(M+1)isopropyl-1H-indol-3-yl]pyrrole-2,5-dione 541.1 1193-(Imidazo[1,2-a]pyridin-3-yl)-4-[5-(3-bromopropoxy)-1-isopropyl-1H-indol-3-yl]pyrrole- 2,5-dione 1203-(Benzofur-7-yl)-4-[5-(2-bromoethoxy)-1-methyl- ES(M+1)1H-indole-3-yl]pyrrole-2,5-dione 465 1212-[4-(2-Bromoethoxy)benzofur-7-yl]acetamide ES 296 (M⁺−1)Reactive Amination:

Preparation 122 1-(1-Benzylpiperidin-4-lyl)-7-methyl-1H-indole

Dissolve 2-(2,2-dimethoxyethyl)-6-methylphenylamine (0.95 g, 4.9 mmol)in acetic acid (20 mL) and add 1-benzylpiperidin-4-one (1 mL, 1.1 eq).Stir for 5 minutes then add sodium triacetoxyborohydride (1.55 g, 1.5eq) and stir at room temperature for 45 minutes. Attach a refluxcondenser and heat to reflux for 2.5 hours. Let cool to room temperaturethen dilute with ethyl acetate. Wash with 5 N sodium hydroxide followedby brine. Dry over magnesium sulfate, filter and concentrate.Purification by column chromatography (1:1 hexanes:ethyl acetate)affords 1.26 g product (85%) as a clear oil. MS (ES, m/z): 305.2 (M+1).

Using a similar method the following compounds may be prepared: PREP. #Product Physical Data 1231-(2,2,6,6-Tetramethylpiperidin-4-yl)-1H-indole ES(M + 1)257.2 1241-(1-Benzylpiperidin-3-yl)-1H-indole ES(M + 1): 291.0 1251-(tert-butoxycarbonyl)-2-methyl-4-indol-1- ES(M + 1): 259.1yl)piperidine 126 4-(6-Chloro-2,3-dihydroindol-1-yl)piperidine-1- MS(ES, m/z): carboxylic acid tert-butyl ester 281.1 1271-(tert-butoxycarbonyl)-4-(5-Chloro-2,3-dihydroindol- ES(M + 1)281.11-yl)piperidine 1281-(tert-butoxycarbonyl)-4-(5-Methyl-2,3-dihydroindol- ES(M + 1)317.21-yl)piperidine 1291-(tert-butoxycarbonyl)-4-(6-Methyl-2,3-dihydroindol- ES(M + 1)317.21-yl)piperidine 1301-(tert-butoxycarbonyl)-4-(5-Chloro-2,3-dihydroindol- ES(M + 1)295.11-yl)-2-methylpiperidine 1311-(tert-butoxycarbonyl)-4-(5-Trifluoromethyl-2,3- ES(M + 1)315.1dihydroindol-1-yl)piperidine 1321-(tert-butoxycarbonyl)-4-(2,3-Dihydroindol-1-yl)-3- ES(M + 1): 403.2methylpiperidine 1333-(6-Fluorobenzofur-7-yl)-4-[1-(1-isopropylpiperidin-4- ES(M + 1): 472.2yl)-1H-indol-3-yl]pyrrole-2,5-dioneN-Alkylation:

Preparation 1345-[3-(tert-Butyldimethylsilyloxy)propoxy]-1-isopropyl-1H-indole

Dissolve 5-[3-(tert-butyldimethylsilyloxy)propoxy]-1H-indole (1.0 g,0.327 mmol) in N,N-dimethylformamide (20 mL) under nitrogen. Add 3.6 mLpotassium tert-butoxide (1M solution in THF, 1.1 equiv) and stir 10minutes, then add 2-iodopropane (0.36 mL, 1.1 eq) and stir for 30minutes. Dilute with ethyl acetate and wash with water then brine. Dryover magnesium sulfate, filter and concentrate. Purification by columnchromography (hexanes to 4:1 hexanes:ethyl acetate) affords 0.43 gproduct (38%) as a clear oil. ¹H NMR (400 MHz, DMSO-d₆) δ 0.00 (s, 6H),0.83 (s, 9H), 1.40 (d, J=6.83 Hz, 6H), 1.86 (m, 2H), 3.74 (m, 2H), 3.98(m, 2H), 4.64 (m, 1H), 6.29 (d, J=2.93 Hz, 1H), 6.71 (m, 1H), 6.99 (d,J=1.95 Hz, 1H), 7.36 (m, 2H).

Using a similar method the following compounds may be made: PREP. #Product Data 135 7-[3-(tert-Butyldimethylsilyloxy)propyl]-1- MS (ES,m/z): isopropyl-2,3-dihydro-1H-indole 334.3 (M + 1) 1361-(acetoxypropyl)-3-indolyl acetonitrile 1372-{1-[3-(tert-Butyldimethylsilyloxy)propyl]- HRMS (ES+):1H-indol-3-yl}acetamide 347.2155. 1382-(1-Isopropyl-1H-indol-3-yl)acetamide 1392-[1-(2-hydroxyethyl)-1H-indol-3- MS (ES, m/z): yl]acetamide 218.9(M + 1) 140 (4-Fluoro-1-isopropyl-1H-indol-3- MS (ES, m/z) yl)oxoaceticacid methyl ester 264 (M⁺ + 1) 141(1-Ethyl-4-fluoro-1H-indol-3-yl)oxoacetic MS (ES, m/z) acid methyl ester250 (M⁺ + 1)Reduction of Indoles to Indolines:

Preparation 142 6-Chloro-2,3-dihydro-1H-indole

Dissolve 6-chloro-1H-indole (2 g, 0.013 mol) in acetic acid (10 mL)under nitrogen. Add sodium cyanoborohydride (1.24 g, 1.5 eq) and stir 20minutes at room temperature. Dilute with ethyl acetate and extract withsodium hydroxide (5 N aqueous). Dry over magnesium sulfate, filter andconcentrate to give 2.35 g (116%) crude product. MS (ES, m/z): 154.0(M+1).

Using a similar method the following compounds may be made: PREP. #Product Physical Data 143 5-Chloro-2,3-dihydro-1H-indole ES(M + 1)154.1144 5-Methyl-2,3-dihydro-1H-indole ES(M + 1)134.1 1456-Methyl-2,3-dihydro-1H-indole ES(M + 1)134.1 1465-Trifluoromethyl-2,3-dihydro-1H-indole ES(M + 1)188.0 1473-(2,3-Dihydro-1H-indol-7-yl)propan-1-ol MS (ES, m/z): 178.1 (M + 1)Oxidation of Indolines to Indoles:

Preparation 148 4-(6-Chloroindol-1-yl)piperidine-1-carboxylic acidtert-butyl ester

Dissolve 4-(6-chloro-2,3-dihydroindol-1-yl)-piperidine-1-carboxylic acidtert-butyl ester (3.1 g, 9.2 mmol) in tetrahydrofuran (50 mL) and coolto 0° C. under nitrogen. Dissolve DDQ (2.1 g, 1 eq) in tetrahydrofuran(25 mL) and add dropwise to the reaction over 15 minutes. Stir for 30minutes at 0° C. Dilute with ethyl acetate then wash with saturatedsodium bicarbonate followed by brine. Dry over magnesium sulfate, filterand concentrate to give 3.15 g (102%) crude product. MS (ES, m/z): 279.1(M+1, product—tert butyl).

Using a similar method described above, the following compounds may bemade: PREP. # Product Physical Data 1494-(5-Chloroindol-1-yl)piperidine-1-carboxylic ES(M + 1) acid tert-butylester 335.1 150 4-(5-Methylindol-1-yl)piperidine-1-carboxylic ES(M + 1)acid tert-butyl ester 259.1 1514-(6-Methylindol-1-yl)piperidine-1-carboxylic ES(M + 1) acid tert-butylester 259.1 152 4-(5-Chloroindol-1-yl)-2-methylpiperidine-1- carboxylicacid tert-butyl ester 153 4-(5-Trifluoromethylindol-1-yl)piperidine-1-ES(M + 1) carboxylic acid tert-butyl ester 313.1 154 Cis4-Indol-1-yl-3-methylpiperidine-1- ES(M + 1) carboxylic acid tert-butylester 403.1 155 7-[3-(tert-Butyldimethylsilyloxy)propyl]-1- MS(ES, m/z):isopropyl-1H-indole 332.3 (M + 1)General Transformations:

Preparation 156 (5-hydroxybenzofur-7-yl)acetic acid ethyl ester

Dissolve 5-methoxybenzofur-7-yl)acetic acid ethyl ester (0.20 g, 0.86mmol) in methylene chloride (10 mL) at −78° C., add boron tribromide(1.08 g, 0.41 mL, 4.3 mmol) and allow to warm to ambient temperature.After 3 h, pour the reaction mixture onto a mixture of ice and water andextract with methylene chloride. Wash the organic extracts with water,brine, dry over sodium sulphate, filter and evaporate to dryness toyield the product (188 mg, quant). ESMS m/z (relative intensity) 221.0(M⁺+H+85).

Preparation 157 2-[1-(1-Benzylpiperidin-4-yl)-1H-indol-3-yl]acetamide

Dissolve trimethylsilyl chloride (2.1 mL, 6 eq) and sodium iodide (2.5g, 6 eq) in acetronitrile (15 mL) and cool to 0° C. while undernitrogen. Dissolve2-[1-(1-benzylpiperidin-4-yl)-1H-indol-3-yl]-2-hydroxyacetamide (1.0 g,2.75 mmol) in acetonitrile (10 mL) and add dropwise to the reaction. Letstir overnight and gradually warm to room temperature. Extract with 5%NaHSO₃ against ethyl acetate then wash with brine. Basify aqueous layerwith saturated sodium bicarbonate and wash with ethyl acetate once more.Combine organic layers and dry over magnesium sulfate. Filter andconcentrate. Triturate from hot diethyl ether to afford product (0.64 g,67%) as a white solid. MS (ES, m/z): 348.0 (M+1).

Preparation 158 2-[4-(2-Diethylaminoethoxy)benzofur-7-yl]acetamide

Combine 2-[4-(2-Bromoethoxy)benzofur-7-yl]acetamide (0.102 g, 0.342mmol) with neat diethyl amine (3 ml, excess), and heat at 55° C. for 18hours. Dilute the mixture with ethyl acetate and wash with water andbrine. Dry over sodium sulfate, filter, and concentrate to give 0.098 g(99%) of the title compound as a brown solid. Mass spectrum:electrospray (m/z) 264 (M⁺+1).

Preparation 1593-(5-Benzyloxybenzofur-7-yl)-4-[1-(3-pyrrolidin-1-ylpropyl)-1H-indol-3-yl]pyrrole-2,5-dione

Dissolve methanesulfonic acid3-{3-[4-(5-benzyloxybenzofur-7-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]indol-1-yl}propylester (220 mg, 0.39 mmol) and pyrrolidine (411 mg, 5.78 mmol) in1-methylpyrrolidine (6 ml) and heat to 55° C. for 5 hours. Allow thereaction to cool to room temperature and stir overnight. Dilute thereaction in ethyl acetate, wash with water and brine, and dry withmagnesium sulfate. Purification by flash chromatography gives the titlecompound (200 mg, 95%). MS(ES⁺): 546.13.

Preparation 1603-(Benzofur-7-yl-4-[1-(1,4-doxa-spiro[4.5]dec-8-yl)-4-fluoro-1H-indol-3-yl]pyrrole-2,5-dione

Dissolve 2-(benzofur-7-yl)acetamide (632 mg, 3.61 mmol) in anhydrousdimethylformamide (DMF) (7.0 mL) and stir under nitrogen. Add[1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-4-fluoro-1H-indol-3-yl]oxoacetic acidmethyl ester (1.56 g, 4.33 mmol) in one portion as a solid. After themixture becomes homogenous, add potassium tert-butoxide intetrahydrofuran (i) (1.0 M, 14.4 mL) in one portion (bolus addition).Warm the reaction to 60° C., and the reaction turns a deep red. Heat thereaction at 60° C. for 1 h, allow to cool to room temperature. Thereaction is monitored by HPLC and TLC, dilute with 200 mL ethyl acetate,wash with saturated sodium bicarbonate solution (1×100 mL), water (1×50mL), and brine (1×50 mL), dry over anhydrous magnesium sulfate. Removethe ethyl acetate by rotovap, and the concentrate. Purify by using flashcolumn chromatography (ethyl acetate/hexanes) to yield 1.49 g (85%) ofthe title compound. MS (ES, m/z): 487.12 (M⁺+1), 485.08(M⁺−1).

The following compounds are prepared in a similar manner: PREP. #Product Physical Data 161 (R)-3-[5-(1-Benzylpyrrolidin-3-yloxy)benzofur-7-yl]-4-(1-methyl-1H-indol-3-yl)pyrrole- 2,5-dione 1623-(5-Benzyloxybenzofur-7-yl)-4-[1-(3- HRMS(ES+):hydroxypropyl)-1H-indol-3-yl]pyrrole- 493.22 2,5-dione

Preparation 1633-(benzofur-7-yl)-4-{1-[1-[N-(tert-butoxycarbonyl)alanyl]piperidin-4-yl]indol-3-yl}pyrrole-2,5-dione

Dissolve the hydrochloride salt of3-(benzofur-7-yl)-4-(1-piperidin-4-yl-1H-indol-3-yl)pyrrole-2,5-dione(0.179 g, 0.36 mmol) in 7.2 mL N,N-dimethylformamide under nitrogen. AddEDCI (0.104 g, 1.5 equivalents), HOBT (0.073 g, 1.5 equivalents),L-Boc-Ala-OH (0.068 g, 1 equivalent), and triethyl amine (0.15 mL, 3 eq)and stir the reaction at 20° C. for 3 hours. Extract with ethyl acetate,wash with 1N hydrochloric acid, saturated sodium bicarbonate, thenbrine. Dry over magnesium sulfate, then filter and concentrate to give0.21 g (100%) the title compound as an orange solid. MS (ES, m/z): 583.1(M+1), 581.2 (M−1).

Transformation of N-methylpyrrolodiones to Benzofuryl:

Preparation 164 3-(trifluoro-methanesulfonic acid benzofur-7-ylester)-4-[1-methyl-1H-indol-3-yl]-1-methylpyrrole-2,5-dione

Add to a stirred solution of7-[4-(1-methylindol-3-yl)-2,5-dioxo-3-pyrrolin-3-yl]benzo[b]fur-4-yl(trifluoromethyl)sulfonate (400 mg, 0.82 mmol) in anhydrousN,N-dimethylformamide (10 ml), potassium carbonate (420 mg) and theniodomethane (0.2 ml, 3.0 mmol). Heat the reaction to 70° C. for 15minutes. Diluted with ethyl acetate, wash with water, brine, dry overmagnesium sulfate, filter and concentrate to afford the title compound(404 mg, 98%) as a yellow solid. MS(ES⁺): 505.0

Preparation 165 3-(trifluoro-methanesulfonic acid benzofur-4-ylester)-4-[1-methyl-1H-indol-3-yl]pyrrole-2,5-dione

Prepare from7-[4-(1-methylindol-3-yl)-2,5-dioxo-3-pyrrolin-3-yl]benzo[b]fur-4-yl(trifluoromethyl)sulfonate according to the Preparation 164. ES(M+1):491.1.

Preparation 1663-(5-Methoxybenzofur-7-yl)-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione

Prepare from3-(5-methoxybenzofur-7-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione(6.9 g, 18.6 mmol) according to the Preparation 164. HRMS: calculated387.1345 found 387.1344.

Preparation 1673-[4-(Benzhydrylideneamino)benzofur-7-yl]-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione

Heat a mixture of7-[1-methyl-4-(1-methylindol-3-yl)-2,5-dioxo-3-pyrrolin-3-yl]benzo[b]fur-4-yl(trifluoromethyl)sulfonate (100 mg, 0.2 mmol), benzophenone imine (0.037ml, 0.22 mmol), tris-(benzylideneacetone)-dipalladium(0)(9 mg, 0.01mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.03mmol), and cesium carbonate (91 mg, 0.28 mmol) in anhydrous toluene (1ml) to 80° C. for 19 hours under a nitrogen atmosphere. Allow thereaction to cool to room temperature, dilute with diethyl ether, andfilter through Celite. Wash the filtrate with water, brine, dry overmagnesium sulfate, filter and concentrate. Flash chromatography oversilica gel (ethyl acetate:hexanes) affords the title compound as a redoil. MS(ES⁺): 536.1.

Preparation 1683-[5-(2-hydroxyethoxy)benzofur-7-yl]-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione

Add to a mixture of3-(5-hydroxybenzofur-7-yl)-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione(2.5 g, 6.7 mmol) and potassium carbonate (2.78 g, 20.1 mmol) inN,N-dimethylformamide (40 ml), 2-(2-bromoethoxy)tetrahydropyran (3.04ml, 20.1 mmol). Heat the mixture to 80° C. under nitrogen atmosphere forovernight. Diluted with ethyl acetate, wash with water, brine, dry overmagnesium sulfate, filter and concentrate to red solid. Dissolve thesolid in methanol (40 ml), add p-toluenesulfonic acid (3 g), stir for 20minutes. Diluted with ethyl acetate, wash with water, brine, dry overmagnesium sulfate, filter and concentrate to afford the title compound(1.88 g, 67%) as a red solid. HRMS: calculated 417.1450 found 417.1462.

Using the method described above the following compounds are made in asubstantially similar manner: PREP. # Product Physical Data 1693-[4-(2-Hydroxyethoxy)benzofur-7-yl]-4-(1- ES(M + 1):iso-propyl-1H-indol-3-yl)-1-methylpyrrole- 445.3 2,5-dione

Preparation 1703-[5-(2-bromoethoxy)benzofur-7-yl]-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione

Add to a solution of3-[5-(2-hydroxyethoxy)benzofur-7-yl]-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione(1.87 g, 4.49 mmol) in dichloromethane (30 ml), triphenylphosphine (1.41g, 5.39 mmol) and carbon tetrabromide (1.79 g, 5.39 mmol). Stir thereaction for 15 minutes under nitrogen atmosphere. Add another 2.2 mmolof triphenylphosphine and 2.2 mmol of carbon tetrabromide and stir for15 more minutes. Diluted with dichloromethane, wash with water, brine,dry over magnesium sulfate, filter and concentrate. Flash chromatographyover silica gel (1% methanol:dichloromethane) affords the title compoundas an orange solid. MS(ES+): 479.0, 481.0.

Using the method described above the following compounds may be made ina substantially similar manner: PREP. # Product Physical Data 1713-[4-(2-Bromoethoxy)benzofur-7-yl]-4- ES(M⁺, M⁺ + 2):(1-isopropyl-1H-indol-3-yl)-1- 507.2, 509.2 methylpyrrole-2,5-dione 1723-[4-(3-Bromopropoxy)benzofur-7-yl]- ES(M+): 521.24-(1-isopropyl-1H-indol-3-yl)-1- methylpyrrole-2,5-dione

Preparation 1733-[5-(2-diethylaminoethoxy)benzofur-7-yl]-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione

Add to a solution of3-[5-(2-bromoethoxy)benzofur-7-yl]-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione(600 mg, 1.25 mmol) in 1-methylpyrrolidine (8 ml), diethylamine (0.65ml, 6.28 mmol). Stir overnight under nitrogen atmosphere. Heat thereaction to 60° C. for 4 hours. Dilute with ethyl acetate, wash withwater, brine, dry over magnesium sulfate, filter and concentrate to redoil. Flash chromatography through SCX column affords the title compoundas a red oil. MS(ES⁺): 472.1; HRMS: calculated 472.2236 found 472.2235.

Using the method described above the following compounds may be made ina substantially similar manner: Physical PREP. # Product Data 1741-Methyl-3-(1-methyl-1H-indol-3-yl)-4-[5- ES(M + 1):(2-morpholin-4-yl-ethoxy)benzofur-7- 486.1 yl]pyrrole-2,5-dione 1753-[4-(2-Diethylaminoethoxy)benzofur-7-yl]-4- ES(M + 1):(1-isopropyl-1H-indol-3-yl)-1-methylpyrrole- 500.3 2,5-dione 1763-[4-(3-Diethylaminopropoxy)benzofur-7-yl]-4- ES(M + 1):(1-isopropyl-1H-indol-3-yl)-1-methylpyrrole- 500.3 2,5-dione

Preparation 1773-(1-(3-methanesulfonyloxyprop-1-yl)indol-3-yl)-4-(5-benzyloxybenzofur-7-yl)pyrrole-2,5-dione

Dissolve3-(5-Benzyloxybenzofur-7-yl)-4-[1-(3-hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione(380 mg, 0.77 mmol) and triethylamine (0.43 ml, 3.1 mmol) intetrahydrofuran (15 ml) and cool in an ice bath. Add methanesulfonylchloride (0.066 ml, 0.85 mmol) dropwise, and stir for four hours. Dilutethe reaction in ethyl acetate, wash with water and brine, dry withmagnesium sulfate, and concentrate to give the title compound (440 mg,100%). MS(ES⁺): 571.14.

Preparation 1783-[5-(2-diethylaminoethoxy)benzofur-7-yl]-4-(1-methyl-1H-indol-3-yl)fur-2,5-dione

Heat a mixture of3-[5-(2-diethylaminoethoxy)benzofur-7-yl]-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione(525 mg, 1.12 mmol) and potassium hydroxide pellets (625 mg, 11.2 mmol)in absolute ethanol (20 ml) to 60° C. for 5 hours. Cool reaction, dilutewith ethyl acetate and water, and the separate layers. Acidify theaqueous layer with 1N hydrochloric acid, concentrate to an orange solid.Dissolve the solid in dichloromethane, wash with water, brine, dry oversodium sulfate, filter and concentrate to afford the title compound (500mg, 98%) as an orange foam. MS(ES+): 491.3.

Using the method described above the following compounds may be made ina substantially similar manner: Physical PREP. # Product Data 1793-(1-Methyl-1H-indol-3-yl)-4-[5-(2-morpholin-4-ylethoxy)benzofur-7-yl]fur-2,5-dione 1803-[4-(2-Diethylaminoethoxy)benzofur-7-yl]-4- ES(M + 1):(1-isopropyl-1H-indol-3-yl)fur-2,5-dione 487.3 1813-[4-(3-Diethylaminopropoxy)benzofur-7-yl]-4- ES(M + 1):(1-isopropyl-1H-indol-3-yl)fur-2,5-dione 501.3

Preparation 182N-{7-[4-(1-Methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydrofur-3-yl]benzofur-4-yl}acetamidea) 3-(4-Aminobenzofur-7-yl)-4-(1-methyl-1H-indol-3-yl)fur-2,5-dione

Heat a mixture of7-[1-methyl-4-(1-methylindol-3-yl)-2,5-dioxo-3-pyrrolin-3-yl]benzo[b]fur-4-yl(trifluoromethyl)sulfonate (60 mg, 0.11 mmol) and potassium hydroxidepellets (62 mg, 1.1 mmol) in absolute ethanol (2 ml) to 70° C. for 3hours. Dilute the reaction with dichloromethane, acidify with 1Nhydrochloric acid, wash with water, brine, dry over magnesium sulfate,filter and concentrate to red solid. Dissolve the crude solid intetrahydrofuran (−5 ml) and add concentrated hydrochloric acid (2drops). Stir the reaction for 5 minutes, concentrate to oil. Purify byflash chromatography over silica gel affords the title compound (40 mg,100%) as a dark red solid. MS(ES⁺): 359.0.

b)N-{7-[4-(1-Methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydrofur-3-yl]benzofur-4-yl}acetamide

Add to a solution of3-(4-aminobenzofur-7-yl)-4-(1-methyl-1H-indol-3-yl)fur-2,5-dione (40 mg,0.11 mmol) in dichloromethane (1 ml), triethylamine (0.046 ml, 0.34mmol), and then acetyl chloride (0.016 ml, 0.22 mmol). Stir the reactionunder nitrogen atmosphere for 10 minutes, dilute with dichloromethane,wash with 1N hydrochloric acid, brine, dry over magnesium sulfate,filter and concentrate to afford the title compound (40 mg, 90%) as ared solid. MS(ES⁺): 401.0.

Preparation 183 10-Oxo-7-aza-spiro[4.5]decane-7-carboxylic acidtert-butyl ester

Dissolve 7-aza-spiro[4.5]decan-10-one (0.43 g, 0.124 mmol) intetrahydrofuran (40 mL). Add sodium hydrogencarbonate (5 mL, saturatedsolution) and di-tert-butyldicarbonate (0.50 g, 0.30 mmol), and stirovernight at room temperature. Wash the solution with water and brine,extracting with ethyl acetate (3×25 mL). Dry over magnesium sulfate,filter and concentrate to afford the title compound. ES(M⁺+H):198.

Preparation 1841-(1-tert-Butoxycarbonyl-3-ethyl-piperidin-4-yl)-1H-indole

Dissolve 1H-Indole (10 g, 50.2 mmol) and2,6-Dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (8.62g, 55.2 mmol) in glacial acetic acid (100 mL), add sodiumtriacetoxyborohydride (15.96 g, 75.3 mmol) and heat the mixture to 70°C. for 20 h. Cool the reaction mixture in an ice bath and made basicwith 5N sodium hydroxide solution. Extract the mixture with methylenechloride, wash with water, brine and dry over sodium sulphate to yieldthe title compound. Flash chromatography using a gradient of ethylacetate in hexanes yields the pure product. ESMS m/z (relativeintensity) ES(M⁺+H): 329.1.

Using the method described above the following compounds are made in asubstantially similar manner: PREP. Physical # Product Data 18510-Indol-1-yl-7-aza-spiro[4.5]decane-7- carboxylic acid tert-butyl ester186 4-(5-Chloroindol-1-yl)-3,3-dimethylpiperidine- ES(M⁺ + H):1-carboxylic acid tert-butyl ester 441.2 1874-Indol-1-ylpiperidine-1,3-dicarboxylic acid 1- ES(M⁺ + H): tert-butylester 3-ethyl ester 317.1

Preparation 1884-(3-Methoxyoxalylindol-1-yl)-2,6-dimethylpiperidine-1-carboxylic acidtert-butyl ester

Dissolve 4-Indol-1-yl-2,6-dimethylpiperidine-1-carboxylic acidtert-butyl ester (0.43 g, 0.124 mmol) in tetrahydrofuran (40 mL). Add2,6-lutidine (0.43 mL, 3 eq) and cool to 0° C. Add oxalyl chloridedropwise and stir for 1.5 hours then cool to −78° C., add methanol (0.1mL, 2 eq) and treated with sodium methoxide (25% w/w in methanol, 22.5mL). Stir for 1 hour then dilute with ethyl acetate and extract withsaturated sodium bicarbonate then brine. Dry over magnesium sulfate,filter and concentrate. Purification by column chromatography (4:1hexanes:ethyl acetate) affords the title compound as the title compound.MS ES(M⁺+H): 415.2.

Using the method described above the following compounds may be made ina substantially similar manner: PREP. # Product Physical Data 18910-(3-Methoxyoxalylindol-1-yl)-7-aza- ES(M⁺ + H):spiro[4.5]decane-7-carboxylic acid 441.2 tert-butyl ester 1904-(5-Chloro-3-methoxyoxalylindol-1-yl)-3,3- ES(M⁺ + H):dimethylpiperidine-1-carboxylic acid tert- 441.2 butyl ester 1913-Hydroxymethyl-4-(3-methoxyoxalylindol- ES(M⁺ + H):1-yl)piperidine-1-carboxylic acid tert-butyl 361.1 ester

Preparation 192 10-Oxo-7-aza-spiro[4.5]decane-7-carboxylic acidtert-butyl ester

Dissolve 7-aza-spiro[4.5]decan-10-one (0.43 g, 0.124 mmol) intetrahydrofuran (40 mL). Add sodium hydrogencarbonate (5 mL, saturatedsolution) and di-tert-butyldicarbonate (0.50 g, 0.30 mmol), and stirovernight at room temperature. Wash the solution with water and brine,extracting with ethyl acetate (3×25 mL). Dry over magnesium sulfate,filter and concentrate to afford the title compound. ES(M⁺+H):198.

Preparation 193 4-Chloro-2-(2,2-dimethoxyethyl)-1-nitrobenzene

Slurry (methoxymethyl)triphenylphosphonium chloride (32.3 g, 93.7 mmol)ir, tetrahydrofuran (350 ml) and cool in an ice-water bath. Add 1.0MKOtBu (94 ml, 94 mmol) in tetrahydrofuran solution to the reactiondropwise via an addition funnel. Stir reaction for one hour, then add5-chloro-2-nitrobenzaldehyde (14.5 g, 78.1 mmol) dropwise as a solutionin 100 ml tetrahydrofuran. Continue to stir in the ice bath for 20minutes, then let warm to ambient temperature. Quench with 0.1 N HCl,extract with ethyl acetate, wash organics with water and brine. Dry withsodium sulfate, filter, concentrate to a brown oil. Purify by flashchromatography (1% EtOAc:Hexanes) to give a crude mix of three spots.Dissolve the crude oil in methanol (200 ml), cool in an ice bath, add 4NHCl in dioxane (30 ml), stir overnight, warming to ambient temperature.Concentrate to brown oil. Purify by flash chromatography, elute withhexanes to 3% EtOAc:hexanes gradient. Yields the title compound (3.7 g,15.1 mmol, 19%).

Preparation 194 3-Hydroxymethyl-4-indol-1-ylpiperidine-1-carboxylic acidtert-butyl ester

Dissolve 1-(1-tert-Butoxycarbonyl-3-ethyl-piperidin-4-yl)-1H-indole(2.86 g, 7.7 mmol) in TIP (25 ml) and stir at ambient temperature. Add a1M solution of lithium aluminum hydride in THF (8.5 ml, 8.5 mmol)dropwise via syringe. Stir for two hours, then quench with 0.34 mlwater, 0.26 ml 5N sodium hydroxide, and 1.2 ml water. Filter through apad of Celite®, concentrate to an oil. Purify by flash chromatography toyield the title compound (1.15 g, 45%). ES (M⁺+1): 275.1

Preparation 1953-(tert-Butyldimethylsilyloxymethyl)-4-indol-1-ylpiperidine-1-carboxylicacid tert-butyl ester

Dissolve 3-Hydroxymethyl-4-indol-1-ylpiperidine-1-carboxylic acidtert-butyl ester (1.1 g, 3.3 mmol) in dichloromethane (20 ml). Addimidazole (340 mg, 5.0 mmol) and tert-butyldimethylsilyl chloride (754mg, 5.0 mmol) and stir at ambient temperature for 72 hours. Dilute withdichloromethane, wash with 1N HCl, water, brine. Dry with sodiumsulfate, filter, and concentrate to an oil. Purify by flashchromatography (10% ethyl acetate:hexanes) to yield the title compound(1.48 g, 100%). ES (M⁺+1): 389.2

Preparation 196{7-[Benzyl-(tert-butoxycarbonyl)aminomethyl]-1-(pyridin-4-yl)-1H-indol-3-ylmethyl}oxoaceticacid methyl ester a) Benzyl-(1H-indol-7-ylmethyl)amine

Add benzyl amine (7.5 g, 69.7 mmol), sodium triacetoxyborohydride (20.7g, 97.5 mmol) and acetic acid (6.0 mL, 104.6 mmol) to a solution of1H-indole-7-carboxaldehyde (10.1 g, 69.7 mmol) in 1,2-dichloroethane(100 mL). Stir at ambient temperature for 24 hours. Dilute withdichloromethane and wash the organic layer with water. Dry withmagnesium sulfate and concentrate. Purify by chromatography (silica gel;ethyl acetate/methanol; 10:0.3 to 10:1) to yield a light yellow solid(13.5 g, 82%). MS (ESI) m/z 237 (M+H)⁺.

b) Benzyl-(1H-indol-7-ylmethyl)carbamic acid tert-butyl ester

Add triethylamine (24 mL, 172 mmol), di-tert-butyl dicarbonate (12.4 g,57.2 mmol) and 4-dimethylaminopyridine (0.7 g, 5.7 mmol) to a solutionof benzyl-(1H-indol-7-ylmethyl)amine (13.5 g, 57.2 mmol) indichloromethane. Stir at ambient temperature for 2 hours. Evaporate thesolvent and purify the residue by chromatography (silica gel;hexane/ethyl acetate; 1:0 to 1:1) to yield a solid (10.0 g, 52%). MSESI) m/z 337 (M+H)⁺.

c) Benzyl-(2,3-dihydro-1H-indol-7-ylmethyl)carbamic acid tert-butylester

Add sodium cyanoborohydride (3.0 g, 47.6 mmol) to a solution ofbenzyl-(1H-indol-7-ylmethyl)carbamic acid tert-butyl ester (10.0 g, 29.8mmol) in acetic acid. Stir the mixture at ambient temperature for 3hours. Dilute with ethyl acetate and cool in an ice bath. Wash themixture with aqueous 3.0 N sodium hydroxide until pH is 8. Dry theorganic layer with magnesium sulfate and concentrate. Purify bychromatography (silica gel; hexane/ethyl acetate; 3:1 to 0:1) to afforda solid as the title compound (5.0 g, 50%). MS (ESI) m/z 339 (M+H)⁺.

d) Benzyl-[1-(pyridinyl)-2,3-dihydro-1H-indol-7-ylmethyl]carbamic acidtert-butyl ester

Bubble nitrogen through benzyl-(2,3-dihydro-1H-indol-7-ylmethyl)carbamicacid tert-butyl ester (3.7 g, 10.9 mmol) in 1,4-dioxane (50 mL) in asealed tube. Mix with 4-bromopyridine hydrochloride (4.3 g, 21.9 mmol),palladium diacetate (0.5 g, 2.18 mmol),2-(dicyclohexylphosphino)biphenyl (0.76 g, 2.18 mmol) and sodiumtert-butoxide (3.1 g, 32.7 mmol). Stir the mixture 110° C. for 16 hours.Cool and filter, then concentrate the filtrate. Purify by chromatography(silica gel; hexane/ethyl acetate; 3:1 to 0:1) to isolate a solid as thetitle compound (1.5 g, 33%). MS (ESI) m/z 416 (M+H)⁺.

e) Benzyl-[1-(pyridin-4-yl)-1H-indol-7-ylmethyl]carbamic acid tert-butylester

Add active manganese dioxide (0.8 g, 9.0 mmol) to a solution ofbenzyl-[1-(pyridin-4-yl)-2,3-dihydro-1H-indol-7-ylmethyl]carbamic acidtert-butyl ester (0.39 mg, 0.94 mmol) in toluene. Stir the mixture at90° C. for 16 hours. Cool and filter, then concentrate the filtrate.Purify by chromatography (silica gel; hexane/ethyl acetate; 3:1 to 0:1)to isolate a solid as the title compound (200 mg, 50%). MS (ESI) m/z 414(M+H)⁺.

f){7-[Benzyl-(tert-butoxycarbonyl)aminomethyl]-1-(pyridin-4-yl)-1H-indol-3-ylmethyl}oxoaceticacid methyl ester

Add five drops of dichloromethane tobenzyl-[1-(pyridin-4-yl)-1H-indol-7-ylmethyl]carbamic acid tert-butylester (700 mg, 1.7 mmol), then cool to −10° C. Add oxalyl chloride (4.0mL, 46.6 mmol) slowly to the mixture. Stir the mixture at ambienttemperature for 4 hours. Dilute with dichloromethane and cool to −78° C.Add triethylamine (16.3 mL, 0.12 mol) and methanol (15 mL) carefully.Wash the organic layer with water, dry with magnesium sulfate, andconcentrate. Purify by chromatography (silica gel; hexane/ethyl acetate;1:1 to 0:1) to isolate a solid as the title product (0.36 mg, 42%). MS(ESI) m/z 500 (M+H)⁺.

Preparation 1974-(7-Methoxymethoxymethyl-3-methoxyoxalylindol-1-yl)piperidine-1-carboxylicacid tert-butyl ester a) 3-(3,3-Dimethoxypropyl)-2-nitrobenzoic acidmethyl ester

Beginning with 3-methyl-2-nitrobenzoic acid methyl ester, the titlecompound is prepared essentially as Preparation 3. ES (M⁺+1) 270.

b) 4-(7-Hydroxymethylindol-1-yl)piperidine-1-carboxylic acid tert-butylester

Hydrogenate 3-(3,3-dimethoxypropyl)-2-nitrobenzoic acid methyl ester(7.8 g, 0.029 mol) in 100 mL of tetrahydrofuran with 0.743 g 5% Pd/C at60 psi for 24 hours. Filter and concentrate. Dissolve the resultingproduct in 30 mL of tetrahydrofuran, and add it dropwise to a suspensionof lithium aluminum hydride (2.2 g, 0.058 mol) in 100 mL oftetrahydrofuran at 0° C. Allow the reaction to warm to room temperature,and stir for 2 hours. Quench the mixture with saturated Rochelle saltand extract with ethyl acetate. Dry and concentrate. Dissolve theproduct in in 30 mL of acetic acid and add 4-oxopiperidine-1-carboxylicacid tert-butyl ester (6.3 g, 0.032 mol). After 10 minutes, add sodiumcyanoborohydride (9.2 g, 0.032 mol) and stir the mixture for 1 hour.Heat the mixture at 100° C. for 3 hours, cool, and pour into water.Neutralize the solution with potassium carbonate and extract with ethylacetate. Dry and concentrate. Dissolve the crude mixture in 100 mL ofmethanol and treat with 20 mL of 1N sodium hydroxide for 3 hours. Removethe methanol in vacuo, and extract the mixture with ethyl acetate. Dryand concentrate. Purify by flash chromatography using 4:1 hexanes/ethylacetate to give 4.1 g of4-(7-hydroxymethylindol-1-yl)piperidine-1-carboxylic acid tert-butylester. FAB MS 330.

c) 4-(7-Methoxymethoxymethyl-indol-1-yl)piperidine-1-carboxylic acidtert-butyl ester

Dissolve 4-(7-hydroxymethylindol-1-yl)piperidine-1-carboxylic acidtert-butyl ester (0.25 g, 0.76 mmol) in 5 mL of tetrahydrofuran and addsodium hydride (36 mg, 1.5 mmol) at room temperature. After 40 minutes,add methoxymethyl chloride (0.11 mL, 1.5 mmol) and stir the mixture for4 hours. Concentrate the reaction and subject it to flash chromatographyusing 5:1 hexanes:ethyl acetate to give 0.23 g product. FAB MS 374.

d)4-(7-Methoxymethoxymethyl-3-methoxyoxalylindol-1-yl)piperidine-1-carboxylicacid tert-butyl ester

Dissolve 4-(7-methoxymethoxymethyl-indol-1-yl)-piperidine-1-carboxylicacid tert-butyl ester (0.36 g, 0.96 mmol) in 20 mL of methylenechloride, cool to 0° C. and add oxalyl chloride (0.093 mL, 1.1 mmol).After 1 hour, add 5 mL of methanol and triethyl amine (0.38 g, 4 mmol)and stir overnight. Flash chromatography using 2:1 hexanes:ethyl acetategives 0.30 g of the title compound.

EXAMPLE 13-(1-Methyl-1H-indol-4-yl)-4-[1-(3-hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione

Add potassium tert-butoxide (4.1 ml, 4.1 mmol, 1M in tetrahydrofuran) toa suspension of 2-[1-(3-hydroxypropyl)-1H-indol-3-yl]acetamide (0.32 g,1.38 mmol) and (1-methyl-1H-indol-4-yl)oxoacetic acid methyl ester (0.30g, 1.38 mmol) in dimethylformamide (10 ml). Stir the reaction at roomtemperature for 12 hours, quench with 1N HCl, and extract into ethylacetate. Wash the organic extract with 5% aqueous lithium chloride andsaturated aqueous sodium chloride, dry over magnesium sulfate, filter,and concentrate under reduced pressure. Chromatograph on flash silicausing a gradient from neat hexanes to 100% ethyl acetate:hexane toobtain the title compound (0.3 g, 54%) as a red solid. ES(M⁺+1)400.2ES(M⁻−1)398.6.

The following compounds may be prepared essentially as described inEXAMPLE 1: EXAMPLE # Product Name Physical Data 23-(1-Methyl-1H-indol-4-yl)-4-[1-(3-hydroxypropyl)- ES(M⁺ + 1) 430.2;6-methoxy-1H-indol-3-yl]pyrrole-2,5-dione ES(M⁻ − 1) 428.2 33-[1-(3-Hydroxypropyl)-1H-indol-4-yl]-4-(1H-indol- ES(M⁺ + 1) 386.2;3-yl)pyrrole-2,5-dione ES(M⁻ − 1) 384.6 43-[1-(3-Hydroxypropyl)-1H-indol-4-yl]-4-[1-(3- ES(M⁺ + 1) 444.2;hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione ES(M⁻ − 1) 442.6 53-(Imidazo[1,2-a]pyridin-5-yl)-4-[1-(3- ES(M⁺ + 1) 387.1;hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione ES(M⁻ − 1) 385.0hydrochloride 6 3-(Imidazo[1,2-a]pyridin-3-yl)-4-[1-(3- ES(M⁺ + 1) 387.2hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 73-(Imidazo[1,2-a]pyridin-3-yl)-4-(1-piperidin-4-yl- ES(M⁺ + 1) 412.2;1H-indol-3-yl)pyrrole-2,5-dione hydrochloride ES(M⁻ − 1) 410.3 83-(Benzofur-7-yl)-4-[5-(2-tert-butoxyethoxy)-1- ES(M⁻ + 1) 257methyl-1H-indole-3-yl]pyrrole-2,5-dione 93-[4-(2-Hydroxyethoxy)benzofur-7-yl]-4-(1H-indol- EI(M⁻ − 1) 287.23-yl)pyrrole-2,5-dione 103-[4-(2-Diethylaminoethoxy)benzofur-7-yl]-4-(4- ES(M⁺ + 1) 504.3fluoro-1-isopropyl-1H-indol-3-yl)pyrrole-2,5-dione hydrochloride 113-[4-(2-Diethylaminoethoxy)benzofur-7-yl]-4-(1- ES(M⁺ + 1) 490.2ethyl-4-fluoro-1H-indol-3-yl)pyrrole-2,5-dione hydrochloride 123-(4-Methoxybenzofur-7-yl)-4-(1-methyl-1H-indol- HRMS (m/z):3-yl)pyrrole-2,5-dione 373.1188. 133-(5-Methoxybenzofur-7-yl)-4-(1-ethyl-1H-indol-3- ES(M⁺ + 1) 387.1yl)pyrrole-2,5-dione 14 3-(5-Methoxybenzofur-7-yl)-4-(1-isopropyl-1H-ES(M⁺ + 1) 401.2 indol-3-yl)pyrrole-2,5-dione 153-(Benzofur-7-yl)-4-(2-isopropyl-1H-indol-3- ES(M⁺ + 1) 371yl)pyrrole-2,5-dione 163-(Benzofur-7-yl)-4-(2-cyclopropyl-1H-indol-3-yl) ES(M⁺ + 1) 369pyrrole-2,5-dione 17 3-(Benzofur-7-yl)-4-(8-hydroxymethyl-6,7,8,9-MS(ES, m/z) tetrahydropyrido[1,2-a]indol-10-yl)pyrrole-2,5-dione413.29(M⁺ + 1) 18 3-(5-Methoxybenzofur-7-yl)-4-(8-hydroxymethyl- MS(ES,m/z) 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrrole- 443.27(M⁺ + 1)2,5-dione 441.40(M⁻ − 1) 193-(5-Fluoro-4-propylbenzofur-7-yl)-4-[1-(piperidine- ES(M⁺ + 1) 572.31-carboxylic acid tert-butyl ester)indol-3-yl]pyrrole- 2,5-dione 203-(4-Methoxybenzofur-7-yl)-4-[1-(4-hydroxybutyl)- ES(M⁺ + 1) 431.11H-indol-3-yl]pyrrole-2,5-dione 213-(Benzofur-7-yl)-4-(1H-indol-3-yl)pyrrole-2,5-dione ES(M⁺ + 1) 329.1 223-(5-Methoxybenzofur-7-yl)-4-[1-(2-hydroxyethyl)- ES(M⁺ + 1) 402.91H-indol-3-yl]pyrrole-2,5-dione 233-(Benzofur-7-yl)-4-[7-(3-hydroxypropyl)-1H-indol- ES(M⁺ + 1) 387.23-yl]pyrrole-2,5-dione 243-(Benzofur-7-yl)-4-[7-(3-hydroxypropyl)-1-methyl- ES(M⁺ + 1) 401.21H-indol-3-yl]pyrrole-2,5-dione 253-(Benzofur-7-yl)-4-[5-(3-hydroxypropoxy)-1- ES(M⁺ + 1) 445.2isopropyl-1H-indol-3-yl]pyrrole-2,5-dione 263-(Benzofur-7-yl)-4-[7-(3-hydroxypropyl)-1- ES(M⁺ + 1) 429.2isopropyl-1H-indol-3-yl]pyrrole-2,5-dione 273-(Benzofur-7-yl)-4-[5-(4-hydroxybutoxy)-1- ES(M⁺ + 1) 459.2isopropyl-1H-indol-3-yl]pyrrole-2,5-dione 283-(5-Fluorobenzofur-7-yl)-4-[5-(4-hydroxybutoxy)-1- ES(M⁺ + 1) 477.2isopropyl-1H-indol-3-yl]pyrrole-2,5-dione 293-(Imidazo[1,2-a]pyridin-3-yl)-4-[5-(3- ES(M⁺ + 1) 445.1hydroxypropoxy)-1-isopropyl-1H-indol-3-yl]pyrrole- 2,5-dione 303-(Isoquinolin-5-yl)-4-[1-(3-hydroxypropyl)-1H- ES(M⁺ + 1) 398.1indol-3-yl]pyrrole-2,5-dione 313-(Isoquinolin-5-yl)-4-(5-methoxy-2-methyl-1H- ES(M⁺ + 1) 384.1indol-3-yl)pyrrole-2,5-dione 323-(Isoquinolin-5-yl)-4-[1-(piperidin-4-yl)-1H-indol- ES(M⁺ + 1) 423.43-yl]pyrrole-2,5-dione 33 3-(Benzofur-7-yl)-4-{1-[1-(tetrahydropyran-4-ES(M⁺ + 1) 524.3 carbonyl)piperidin-4-yl]-1H-indol-3-yl}pyrrole-2,5-dione 34 3-(Benzofur-7-yl)-4-{1-[1-(tetrahydropyran-4- ES(M⁺ + 1) 510.3ylmethyl)piperidin-4-yl]-1H-indol-3-yl}pyrrole-2,5- dione hydrochloride35 3-(Benzofur-7-yl)-4-[1-tetrahydropyran-4-yl)-1H- ESMS m/z: 413.1indol-3-yl]pyrrole-2,5-dione (M⁺ + 1) 363-(6-Fluorobenzofur-7-yl)-4-[1-(1-benzylpiperidin-3- HRMS(M⁺ + 1)yl)-1H-indol-3-yl]pyrrole-2,5-dione 520.2036 373-(Furo[3,2-c]pyridin-7-yl)-4-[1-(piperidine-1- ES(M⁺ + 1) 513.2carboxylic acid tert-butyl ester)indol-3-yl]pyrrole- 2,5-dione 383-(Benzofur-7-yl)-4-{5,6-difluoro-7-[1-(carboxylic ES(M⁺+ 1) 577.2 acidtert-butyl ester)-2-methylpiperazin-4-yl]-1-methyl-1H-indol-3-yl}pyrrole-2,5-dione 393-(6-Fluorobenzofur-7-yl)-4-[1-(2,2,6,6- ES(M⁺ + 1) 486.2tetramethylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5- dionehydrochloride 40 3-(Imidazo[1,2-a]pyridin-3-yl)-4-(1-isopropyl-1H-ES(M⁺ + 1) 371.2 indol-3-yl)pyrrole-2,5-dione 413-(Benzofur-7-yl)-4-[4-fluoro-1-(piperidin-4-yl)-1H- ES(M⁺ + 1) 430.2indol-3-yl]pyrrole-2,5-dione hydrochloride 423-(4-Chlorobenzofur-7-yl)-4-[1-(piperidin-4-yl)-1H- HRMS(M + H)indol-3-yl]pyrrole-2,5-dione 446.1266 433-(5-Fluoro-4-propylbenzofur-7-yl)-4-[1-(piperidin- HRMS(M + H)4-yl)-1H-indol-3-yl]pyrrole-2,5-dione 472.2034 443-(5-Chloro-4-fluorobenzofur-7-yl)-4-[1-(piperidin- HRMS(M + H)4-yl)-1H-indol-3-yl]pyrrole-2,5-dione 464.1162 453-(4-Methylsulfanylbenzofur-7-yl)-4-[1-(piperidin-4- HRMS(M + H)yl)-1H-indol-3-yl]pyrrole-2,5-dione 458.1552 463-(4,6-Difluorobenzofur-7-yl)-4-[1-(piperidin-4-yl)- HRMS(M + H)1H-indol-3-yl]pyrrole-2,5-dione 448.1482 473-(5,6-Difluorobenzofur-7-yl)-4-[1-(piperidin-4-yl)- ESMS(M⁻ − 1)m/z:1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 446.3 483-(4,5-Difluorobenzofur-7-yl)-4-[1-(piperidin-4-yl)- ESMS(M⁻ − 1)m/z:1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 446.3 493-(6-Fluorobenzofur-7-yl)-4-[1-(piperidin-4-yl)-1H- ES(M⁺ + H) 430.0indol-3-yl]pyrrole-2,5-dione hydrochloride 503-(5-Chlorobenzofur-7-yl)-4-[1-(piperidin-4-yl)-1H- ESMS(M⁺ + H)m/z:indol-3-yl]pyrrole-2,5-dione hydrochloride 446.1 513-(6-Fluorobenzofur-7-yl)-4-[1-(2-methylpiperidin- HRMS(M + 1):4-yl)-1H-indol-3yl]pyrrole-2,5-dione hydrochloride 444.1723 523-(6-Fluorobenzofur-7-yl)-4-[1-(2,6- ES(M⁺ + H): 458.2dimethylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5- dione hydrochloride53 3-(6-Fluoro-2,3-dihydrobenzofour-7-yl)-4-[1-(7-aza- ES(M⁺ + H): 486.2spiro[4.5]dec-10-yl)-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 543-(6-Flourobenzofur-7-yl)-4-[1-(7-aza-spiro[4.5]dec- ES(M⁺ + H): 484.210-yl)-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 55 Cis3-(Imidazo[1,2-a]pyridin-3-yl)-4-[1-(2- HRMS(M + 1):methylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5- 426.1942 dionehydrochloride 56 Trans 3-(Imidazo[1,2-a]pyridin-3-yl)-4-[1-(2- HRMS(M +1): methylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5- 426.1936 dionehydrochloride 57 3-(Imidazo[1,2-a]pyridin-3-yl)-4-[5-chloro-1-(3,3-HRMS(M + 1): dimethylpiperidin-4-yl)-1H-indol-3-yl]pyrrole- 474.17042,5-dione hydrochloride 58 3-(6-Fluorobenzofur-7-yl)-4-[5-Chloro-1-(3,3-ES(M⁺ + H): 492.1 dimethylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 593-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-[5-Chloro- ES(M⁺ + H): 494.11-(3,3-dimethylpiperidin-4-yl)-1H-indol-3- yl]pyrrole-2,5-dionehydrochloride 60 Cis 3-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-[1-(2-ES(M⁺ + H): 446.1 methylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5- dionehydrochloride 61 3-(6-Fluorobenzofur-7-yl)-4-[1-(3- ES(M⁺ + H): 412.2hydroxymethylpiperidin-4-yl)-1H-indol-3-yl]pyrrole- 2,5-dionehydrochloride 62 3-(6-Fluorobenzofur-7-yl)-4-[7-(benzylamino- MS(M + H)543 methyl)-1-(pyridin-4-yl)-1H-indol-3-yl]pyrrole-2,5- dione 633-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-[7- MS(M + H) 545(benzylaminomethyl)-1-(pyridin-4-yl)-1H-indol-3- yl]pyrrole-2,5-dione 643-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-[7- MS(M + H) 506methoxymethoxymethyl-1-(piperidin-4-yl)-1H-indol- 3-yl]pyrrole-2,5-dione65 3-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-[7- MS(M + H) 462hydroxymethyl-1-(piperidin-4-yl)-1H-indol-3- yl]pyrrole-2,5-dione 663-(Imidazo[1,2-a]pyridin-3-yl)-4-((1-(1-tert- MS(M + H) 546.2butoxycarbonyl)piperidin-4-yl)-6-chloroindol-3- yl)pyrrole-2,5-dione

EXAMPLE 673-(Benzofur-7-yl)-4-{1-[1-(2-alaninyl)piperidin-4-yl]-1H-indol-3-yl}pyrrole-2,5-dione

Dissolve(2-{4-[3-(4-(benzofur-7-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)indol-1-yl]piperidin-1-yl}-1-methyl-2-oxoethyl)carbamicacid tert-butyl ester (0.21 g, 0.36 mmol) in dichloromethane (30 mL) andadd hydrochloric acid in dioxane (4N, 10 mL) while under nitrogen. After3 hours, dilute with diethyl ether and filter off the orange precipitateto give 0.123 g (66%) of the title compound. High Res. Mass Spec (m/z):Calcd 483.2032 Found 483.2040.

The following compounds may be prepared in a similar manner as EXAMPLE67: Example # Product Name Physical Data 683-(Benzofur-7-yl)-4-[1-isopropyl-5-(piperidin-4- ES(M⁺ + H)ylmethoxy)-1H-indol-3-yl]pyrrole-2,5-dione 484.2 693-(5,6-Difluorobenzofur-7-yl)-4-[1-(2- ES(M⁺ + H): 462.2methylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5- dione hydrochloride 703-(5,6-Difluorobenzofur-7-yl)-4-[1-(2- ES(M⁺ + H): 462.2methylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5- dione hydrochloride 713-(6-Fluorobenzofur-7-yl)-4-[1-(3- ES(M⁺ + H): 444.2methylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5- dione 723-(6-Fluorobenzofur-7-yl)-4-[1-(2- ES(M⁺ + H): 444.2methylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5- dione hydrochloride 733-(6-Fluorobenzofur-7-yl)-4-[1-(2- ES(M⁺ + H): 444.2methylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5- dione hydrochloride 743-(Furo[3,2-c]pyridin-7-yl)-4-[1-(piperidin-4-yl)- ES(M⁺ + H) 413.21H-indol-3-yl]pyrrole-2,5-dione hydrochloride 753-(Benzofur-7-yl)-4-[5,6-difluoro-1-methyl-7-(3- ES(M⁺ + H) 477.2methylpiperazin-1-yl)-1H-indol-3-yl]pyrrole-2,5- dione hydrochloride 763-(6-Fluorobenzofur-7-yl)-4-[6-chloro-1- ES(M⁺ + H) 464.1(piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 773-(6-Fluorobenzofur-7-yl)-4-[5-chloro-1- ES(M⁺ + H)(piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione 464.1 hydrochloride 783-(6-Fluorobenzofur-7-yl)-4-[5-methyl-1- ES(M⁺ + H) 444.2(piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 793-(6-Fluorobenzofur-7-yl)-4-[6-methyl-1- ES(M⁺ + H) 444.2(piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 803-(6-Fluorobenzofur-7-yl)-4-[1-(piperidin-4-yl)-5- HRMS 498.1446trifluoromethyl-1H-indol-3-yl)pyrrole-2,5-dione hydrochloride 813-(6-Fluorobenzofur-7-yl)-4-[5-chloro-1-(2- ES(M⁺ + H)methylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5- 478.1 dionehydrochloride 82 3-(6-Fluorobenzofur-7-yl)-4-[5-chloro-1-(2- ES(M⁺ + H)methylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5- 478.1 dionehydrochloride 83 3-(Imidazo[1,2-a]pyridin-3-yl)-4-[5-chloro-1- ES(M⁺ +H) (piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione 446.1 hydrochloride84 3-(2,2-Difluorobenzo[1,3]dioxol-4-yl)-4-[1- ES(M⁺ + H)(piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione 452.1 hydrochloride 853-(Benzo[1,3]dioxol-4-yl)-4-[1-(piperidin-4-yl)- ES(M⁺ + H)1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 416.1 863-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-[1- ES(M⁺ + H)(piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione 432.1 hydrochloride 873-(6-Fluorobenzofur-7-yl)-4-[5-methoxy-1- ES(M⁺ + H)(piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione 460.1 hydrochloride 883-(2,3-Dihydro-6-fluorobenzofur-7-yl)-4-[5- ES(M⁺ + H)chloro-1-(piperidin-4-yl)-1H-indol-3-yl]pyrrole- 466.1 2,5-dionehydrochloride 89 3-(2,3-Dihydrobenzofur-7-yl)-4-[1-(piperidin-4- ES(M⁺ +H) yl)-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 414.1 903-(2,3-Dihydro-6-fluorobenzofur-7-yl)-4-[5-(3- ES(M⁺ + H)hydroxyprop-1-yl)-1-(isopropyl)-1H-indol-3- 465.1 yl]pyrrole-2,5-dionehydrochloride 91 3-(2,3-Dihydro-5,6-difluorobenzofur-7-yl)-4-[1- ES(M⁺ +H) (piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione 450.1 hydrochloride92 3-(2,3-Dihydro-3-methyl-6-fluorobenzofur-7-yl)- ES(M⁺ + H)4-[1-(piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5- 446.1 dionehydrochloride 93 3-(2,3-Dihydro-6-fluorobenzofur-7-yl)-4-[1-(3,3-ES(M⁺ + H) dimethylpiperidin-4-yl)-1H-indol-3-yl]pyrrole- 460.12,5-dione hydrochloride 94 3-(2,3-Dihydro-4-methoxybenzofur-7-yl)-4-[1-ES(M⁺ + H) (piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione 444.1hydrochloride 95 3-(2,3-Dihydro-4-methoxybenzofur-7-yl)-4-[1- ES(M⁺ + H)(3,3-dimethylpiperidin-4-yl)-1H-indol-3- 442.2 yl]pyrrole-2,5-dionehydrochloride 96 3-(Furo[3,2-c]pyridin-7-yl)-4-[1-(3,3-dimethyl- ES(M⁺ +H) piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione 441.1 hydrochloride97 3-(2,3-Dihydro-6-fluorobenzofur-7-yl)-4-[1- ES(M⁺ + H)(piperidin-4-yl)-7-methyl-1H-indol-3-yl]pyrrole- 446.2 2,5-dionehydrochloride

EXAMPLE 983-(5-Methoxybenzofur-7-yl)-4-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]pyrrole-2,5-dione

Dissolve3-(5-methoxybenzofur-7-yl)-4-[1-(3-hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione(0.058 g, 0.118 mmol) in 10 mL dichloromethane. Add carbon tetrabromide(0.077 g, 1 equivalent) and triphenyl phosphine (0.061 g, 1 equivalent).Stir for 10 min, add another equivalent of both reagents. Stir 10 minthen dilute with dichloromethane and wash with water followed by brine.Dry over magnesium sulfate then filter and concentrate. Purification bycolumn chromatography (2% methanol:dichloromethane) affords the3-(5-methoxybenzofur-7-yl)-4-[1-(3-bromopropyl)-1H-indol-3-yl)pyrrole-2,5-dione.3-(5-Methoxybenzofur-7-yl)-4-[1-(3-bromopropyl)-1H-indol-3-yl]pyrrole-2,5-dioneis dissolved in 1.5 mL 1-methyl-2-pyrrolidinone and add dimethylamine(2M solution in tetrahydrofuran, 0.3 mL, 5 equivalents). Heat to 60° C.for 16 hrs. Extract with ethyl acetate versus water, concentrate organiclayer. Redissolve in a minimal amount of methanol and load onto an SCX™Varian column (pretreated with a 5% acetic acid: methanol solution).Wash with methanol and ethyl acetate to remove impurities, flush with 2Mammonia methanol to recover product. ES(M⁺+H)444.0.

The following compounds are prepared in similar manner as describedabove. Physical Example # Product Data  993-(5-Methoxybenzofur-7-yl)-4-[1-(2-dimethylaminoethyl)- ES(M⁺ + H)1H-indol-3-yl]pyrrole-2,5-dione 430.0 1003-(5-Methoxybenzofur-7-yl)-4-{1-[2-(4-methylpiperazin-1- ES(M⁺ + H)yl)ethyl]-1H-indol-3-yl}pyrrole-2,5-dione 485.0 1013-(Benzofur-7-yl)-4-[7-(3-diethylaminopropyl)-1H-indol-3- ES(M⁺ + H)yl]pyrrole-2,5-dione 442.2 1023-(Benzofur-7-yl)-4-[7-(3-diethylaminopropyl)-1-methyl- ES(M⁺ + H)1H-indol-3-yl]pyrrole-2,5-dione 456.3 1033-(Benzofur-7-yl)-4-[5-(3-diethylaminopropoxy)-1- ES(M⁺ + H)isopropyl-1H-indol-3-yl]pyrrole-2,5-dione 500.2 1043-(Benzofur-7-yl)-4-{1-isopropyl-5-[3-(piperidin-1- ES(M⁺ + H)yl)propoxy]-1H-indol-3-yl}pyrrole-2,5-dione 512.3 1053-(Benzofur-7-yl)-4-{5-[3-(4-hydroxypiperidin-1- ES(M⁺ + H)yl)propoxy]-1-isopropyl-1H-indol-3-yl}pyrrole-2,5-dione 528.2 1063-(Benzofur-7-yl)-4-[5-(4-diethylaminobutoxy)-1-isopropyl- ES(M⁺ + H)1H-indol-3-yl]pyrrole-2,5-dione 514.2 1073-(Benzofur-7-yl)-4-[7-(3-diethylaminopropyl)-1-isopropyl- ES(M⁺ + H)1H-indol-3-yl]pyrrole-2,5-dione 484.2 1083-(5-Fluorobenzofur-7-yl)-4-[5-(4-diethylaminobutoxy)-1- ES(M⁺ + H)isopropyl-1H-indol-3-yl]pyrrole-2,5-dione 532.3 1093-(5,6-Difluorobenzofur-7-yl)-4-[5-(4-diethylaminobutoxy)- ES(M⁺ + H)1-isopropyl-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 550.2 1103-(6-Fluorobenzofur-7-yl)-4-[5-(4-diethylaminobutoxy)-1- ES(M⁺ + H)isopropyl-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 532.2 1113-(Imidazo[1,2-a]pyridin-3-yl)-4-[5-(3-diethylamino- ES(M⁺ + H)propoxy)-1-isopropyl-1H-indol-3-yl]pyrrole-2,5-dione 500.2 1123-[4-(3-Dimethylaminopropoxy)benzofur-7-yl]-4-(1-methyl- ESMS1H-indol-3-yl)pyrrole-2,5-dione hydrochloride (M⁺ + H)m/z: 444.2 1133-[5-(2-Morpholin-4-ylethoxy)benzofur-7-yl]-4-(1-methyl- HRMS(M + H)1H-indol-3-yl)pyrrole-2,5-dione hydrochloride 472.1880 1143-(5-Fluorobenzofur-7-yl)-4-[5-(3-diethylaminopropoxy)-1- ES(M⁺ + H)isopropyl-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 518.3 1153-(Furo[3,2-c]pyridin-7-yl)-4-[7-(3-diethylaminopropyl)-1- ES(M⁺ + H)isopropyl-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 485.3 1163-(Furo[3,2-c]pyridin-7-yl)-4-[5-(3-diethylaminopropoxy)-1- ES(M⁺ + H)isopropyl-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 501.3 1173-(Benzofur-7-yl)-4-{5-[3-(4-acetylpiperazin-1-yl)propoxy]- ES(M⁺ + H)1-isopropyl-1H-indol-3-yl}pyrrole-2,5-dione hydrochloride 555.2 1183-(4-Methoxybenzofur-7-yl)-4-[1-(3-dimethylaminopropyl)- HRMS(m/z):1H-indol-3-yl]pyrrole-2,5-dione 458.2078 119 3-(Benzofur-7-yl)-4-{5-[2-ES(M⁺ + 1) (cyclopropylmethylamino)ethoxy]-1-methyl-1H-indol-3- 456yl}pyrrole-2,5-dione hydrochloride 1203-(Benzofur-7-yl)-4-[5-(2-ethylaminoethoxy)-1-methyl-1H- ES(M⁺ + 1)indol-3-yl]pyrrole-2,5-dione hydrochloride 430 1213-(Benzofur-7-yl)-4-[5-(2-benzylaminoethoxy)-1-methyl- ES(M⁺ + 1)1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 492 1223-(Benzofur-7-yl)-4-[5-(2-diethylaminoethoxy)-1-methyl- ES(M⁺ + 1)1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 458 1233-(Benzofur-7-yl)-4-[1-methyl-5-(2-piperazin-1-ylethoxy)- ES(M⁺ + 1)1H-indol-3-yl]pyrrole-2,5-dione dihydrochloride 471 1243-(5-Fluorobenzofur-7-yl)-4-[7-(3-diethylaminopropyl)-1- ES(M⁺ + H)isopropyl-1H-indol-3-yl]pyrrole-2,5-dione 502.3 1253-(5-Hydroxybenzofur-7-yl)-4-[1-(3-pyrrolidin-1-ylpropyl)- HRMS(M + H)1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 492.1625

EXAMPLE 126 3-[5-(carbamic acid methylester)benzofur-7-yl]-4-[1-methyl-1H-indol-3-yl]pyrrole-2,5-dione

Cool a solution of3-(5-aminobenzofur-7-yl)-4-(1-methyl-1H-indol-3-yl)furo-2,5-dione (30mg, 0.084 mmol) in dichloromethane (1 ml) to a −78° C., addtriethylamine (0.035 ml, 0.25 mmol) and methyl chloroformate (0.013 ml,0.17 mmol) dropwise. Stir the reaction for 10 minutes, warm to 20° C.Diluted with ethyl acetate, wash with water, brine, dry over magnesiumsulfate, filter and concentrate to an orange solid. Dissolve crude solidin N,N-dimethylformamide (1 ml), methanol (0.1 ml), add1,1,1,3,3,3-hexamethyl-disilazane (0.2 ml). Heat the reaction to 80° C.for 5 hours, dilute with ethyl acetate, wash with water, 0.1Nhydrochloric acid, brine, dry over magnesium sulfate, filter andconcentrate to an orange film. Flash chromatography over silica gel (40%ethyl acetate:hexanes) affords the title compound (6 mg) as an orangesolid.

HRMS (M+H) 416.1248

EXAMPLE 1273-(5-(N-methanesulfonamide)benzofur-7-yl)-4-[1-methyl-1H-indol-3-yl]pyrrole-2,5-dione

Follow similar procedure as in Example 96, starting with3-(5-aminobenzofur-7-yl)-4-(1-methyl-1H-indol-3-yl)furo-2,5-dione (20mg, 0.056 mmol) and methanesulfonyl chloride (0.004 ml, 0.056 mmol).Flash chromatography over silica gel (40% ethyl acetate:hexanes) affordsthe title compound (8 mg) as an orange solid.

HRMS (M+H) 436.0939.

EXAMPLE 1283-(6-Fluorobenzofur-7-yl)-4-{1-[1-(2-glycyl)piperidin-4-yl]-1H-indol-3-yl}pyrrole-2,5-dione

Combine3-(6-fluorobenzofur-7-yl)-4-[1-(piperidin-4-yl]-1H-indol-3-yl]pyrrole-2,5-dione(90 mg, 0.22 mmol), tert-butoxycarbonylamino-acetic acid (40 mg, 0.22mmol), 4-N,N-dimethylaminopyridine (10 mg), triethylamine (0.091 ml,0.66 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (63 mg, 0.33 mmol) in dichloromethane (5 ml) and stir atroom temperature overnight. Purify the crude reaction mixture by a 10gram SCX™ Varian column, wash column with methanol, and then wash theproduct off with 2.0M ammonia in methanol solution. Concentrate theproduct fractions to a yellow solid, triturate with ether to give thetitle compound as a yellow solid. HRMS (ES+): 487.1779.

Using the method described in Example 128, the following compounds maybe made in a substantially similar manner: EXAMPLE Physical # ProductData 129 3-(6-Fluorobenzofur-7-yl)-4-{1-[1-(2- HRMS(M + H)methylamino-acetyl)piperidin-4-yl]-1H- indol-3-yl}pyrrole-2,5-dione501.1948 130 3-(Imidazo[1,2-a]pyridin-3-yl)-4-{1- HRMS(M + H)[1-(piperidine-4-carbonyl)piperidin-4- yl]-1H-indol-3-yl}pyrrole-2,5-dione hydrochloride 501.1948

EXAMPLE 1313-(4-Hydroxybenzofur-7-yl)-4-[1-(3-hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione

Dissolve3-(4-methoxybenzofur-7-yl)-4-[1-(3-hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione(0.1 g, 0.24 mmol) in 2.5 mL dichloromethane under nitrogen at −78° C.Add boron tribromide (0.11 mL, 1.16 mmol, 5 equiv) dropwise and stir at−78° C. for 1 hr, warm to room temperature and stir for 1 hr. Quench thereaction with ice and then extract with ethyl acetate. Washed theorganics with brine, dry over sodium sulfate, filter, and concentrate invacuo. Purification by column chromatography (25% ethyl acetate:hexanesto 50% ethyl acetate:hexanes) afforded 0.050 g (52%) of the titleproduct. High Res. Mass Spec (m/z): Calcd 403.1301 Found 403.1294.

The following compounds may be prepared in a similar manner as inEXAMPLE 131: EXAMPLE Physical # Product Data 1323-(5-Hydroxybenzofur-7-yl)-4-(1-methyl- ES(M⁺ + H)1H-indol-3-yl)pyrrole-2,5-dione 359.1 1333-(4-Hydroxybenzofur-7-yl)-4-(1H-indol-3- ES(M⁺ + H)yl)pyrrole-2,5-dione 345.0 134 3-(4-Hydroxybenzofur-7-yl)-4-[1-(4-ES(M⁺ + H) hydroxybutyl)1H-indol-3-yl]pyrrole-2,5- 417.0 dione 1353-(4-Hydroxybenzofur-7-yl)-4-(1-methyl- ES(M⁺ + H)1H-indol-3-yl)pyrrole-2,5-dione 359.1

EXAMPLE 1363-(5-Hydroxybenzofur-7-yl)-4-[1-(piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione

Combine3-(5-methoxybenzofur-7-yl)-4-[1-(piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione(0.125 g, 0.24 mmol) and pyridine hydrochloride (2.2 g, 18-fold excessby weight) under nitrogen. Attach a heating mantle and heat to 190° C.for 45 min. Let cool to 20° C., then extract with ethyl acetate versuswater. Wash with brine, dry organic layer over magnesium sulfate, filterand concentrate. Purification by column chromatography (5%methanol:dichloromethane) gives 0.085 g (70%) product. High Res. MassSpec (m/z): Calcd 518.2080 found 518.2080.

EXAMPLE 1373-[5-(Piperidin-4-yloxy)benzofur-7-yl]4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-one

Dissolve3-[5-(1-benzylpiperidin-4-yloxy)benzofur-7-yl]-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione(0.050 g, 0.094 mmol) in 1,2-dichloroethane (10 mL) under nitrogen andadd 1-chloroethyl chloroformate (61 μL). Heat to reflux for 4 hours,then add methanol (20 mL) and heat for an additional 1.5 hours. Cool to20° C., then concentrate and redissolve in 1 mL N,N-dimethylformamide.Purification by reverse phase affords 0.018 g of the title product asthe hydrochloride salt. High Res. Mass Spec (m/z): Calcd 442.1767 Found442.1762.

The following compounds may be prepared in a similar manner as EXAMPLE137: EXAMPLE # Product Physical Data 1383-(Imidazo[1,2-a]pyridin-3-yl)-4-[1-(3,3-dimethylpiperidin- HRMS(M + 1):4-yl)-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 442.1762 1393-(Benzofur-7-yl)-4-[1-(piperidin-4-yl)-1H-indol-3- ES(M⁺ + H)yl]pyrrole-2,5-dione 412.2 140(R)-3-[5-(Pyrrolidin-3-yloxy)benzofur-7-yl]-4-(1-methyl- ESMS(M⁺ + H)1H-indol-3-yl)pyrrole-2,5-dione hydrochloride m/z 428.1 1413-(5-Fluorobenzofur-7-yl)-4-[1-(piperidin-3-yl)-1H- HRMS(M + 1):indol-3-yl]pyrrole-2,5-dione hydrochloride 430.1567 1423-(6-Fluorobenzofur-7-yl)-4-[1-(piperidin-3-yl)-1H- HRMS(M + 1):indol-3-yl]pyrrole-2,5-dione hydrochloride 430.1567 1433-(6-Fluorobenzofur-7-yl)-4-[7-methyl-1-(piperidin-4- ES(M⁺ + H) 444.1yl)-1H-indol-3-yl]pyrrole-2,5-dione hydrochloride 1443-(4-Methoxybenzofur-7-yl)-4-[1-(piperidin-4-yl)-1H- HRMS(m/z):indol-3-yl]pyrrole-2,5-dione 442.1767 1453-(5-Hydroxybenzofur-7-yl)-4-[1-(3-hyroxypropyl)-1H- ES(M⁺ + H)indol-3-yl]pyrrole-2,5-dione 403.19

EXAMPLE 1463-(Benzofur-7-yl)-4-[N-(endo-8-azabicyclo[3.2.1]octan-3-yl)-1H-indol-3-yl]pyrrole-2,5-dionehydrochloride

Add3-(benzofur-7-yl)-4-[N-(endo-8-carbethoxy-8-azabicyclo[3.2.1]octan-3-yl)-1H-indol-3-yl]pyrrole-2,5-dione(220 mg, 0.43 mmol) with pyridine HCl (1 g, 8.65 mmol) and heat to 160°C. in an argon atmosphere for 2 h. Cool the reaction mixture and pourinto water (100 ml). After addition of sodium hydroxide (1 g, 25 mmol),extract the aqueous solution with dichloromethane. Evaporate the organiclayer and stir the remaining solid with 10% HCl in dioxane (3 mL).Filter the resulting solid and dry in vacuo to afford 160 mg of thetitle compound as red crystals. ES(M⁺+H): 438.2.

EXAMPLE 1473-(4-Hydroxybenzofur-7-yl)-4-(2-chloro-1-methyl-1H-indol-3-yl)pyrrole-2,5-dione

Dissolve3-(4-hydroxybenzofur-7-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione(0.25 g, 0.70 mmol) in 50 mL chloroform under nitrogen. Add 0.093 g(0.70 mmol, 1 equiv) N-chloro succinimide and attach a reflux condenser.Heat to 50° C. and let go overnight. Let cool to room temperature, thenextract with ethyl acetate versus water. Wash with brine, then dry oversodium sulfate. Filter and concentrate in vacuo. Purification by columnchromatography (20% ethyl acetate:hexanes) yields 0.034 g (12%) product.High Res. Mass Spec (m/z): Calcd 393.0655 Found 393.0642.

EXAMPLE 1483-(Benzofur-7-yl)-4-[1-(4-oxocyclohexyl)-1H-indol-3-yl]pyrrole-2,5-dione

Dissolve3-(Benzofur-7-yl)-4-[1-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-fluoro-1H-indol-3-yl]pyrrole-2,5-dione(1.40 g, 2.88 mmol) in tetrahydrofuran (20 mL) and stir at roomtemperature. Add 1N hydrochloric acid (20 mL) and heat the reaction toreflux for 24 h. Upon completion, Filter the product, rinse with coldwater, and dry under vaccuum. The orange solid is used without furtherpurification, 1.1 g (87%). MS (ES, m/z): 443.18(M⁺+1), 441.13(M⁺−1).

The following compound may be prepared as described in EXAMPLE 148:EXAMPLE # Product Name Physical Data 1493-(6-Fluorobenzofur-7-yl)-4-[1-(4- ES(M⁺ + H): 443.2oxocyclohexyl)-1H-indol-3- yl]pyrrole-2,5-dione

EXAMPLE 1503-(Benzofur-7-yl)-4-[4-fluoro-1-(4-trans-isobutylaminocyclohexyl)-1H-indol-3-yl]pyrrole-2,5-dionehydrochloride

Add to a suspension of3-(benzofur-7-yl)-4-[4-fluoro-1-(4-oxocyclohexyl)-1H-indol-3-yl]pyrrole-2,5-dione(1.26 mmol, 0.678 g) in anhydrous tetrahydrofuran (3 mL), isobutylamine(12.6 mmol) and a drop of glacial acetic acid, stir at room temperatureunder nitrogen for several hours. Add sodium triacetoxyborohydride (2.52mmol, 0.534 g) in two portions, and stir at room temperature overnight.Upon completion by TLC (use 1:1 ethyl acetate/hexanes with 10% triethylamine), dilute the reaction with ethyl acetate (300 mL) and wash withsaturated sodium bicarbonate solution (100 mL). Separate the two phases,wash the organic layer with water (50 mL), brine (50 mL), dry overanhydrous sodium sulfate, and concentrate. Purify the residue by flashcolumn chromatography (ethyl acetate/hexanes with 10% triethyl amine) toisolate the free amine product. Dissolve the amine (0.556 mmol) inmethanol (3 mL) and concentrate hydrochloric acid is added (0.030 g,0.600 mmol), heat the reaction to 45° C. under nitrogen for 30 min. Coolto room temperature, then in an ice bath. Filter the hydrochloridecrystals and dry to yield the title compound.

MS(ES,m/z):C30H30FN3O3.ClH: 500.38 (M⁺+1), 498.11 (M⁺−1).

The following compounds are prepared as EXAMPLE 150: EXAMPLE # ProductName Physical Data 151 3-(Benzofur-7-yl)-4-[4-fluoro-1-(4-cis- MS(ES,m/z) isobutylaminocyclohexyl)-1H-indol-3-yl]pyrrole-2,5- (M⁺ + H) 500.42dione hydrochloride 152 3-(Benzofur-7-yl)-4-[1-(4-cis-pyrrolidin-1-MS(ES, m/z) 480.41 ylcyclohexyl)-1H-indol-3-yl]pyrrole-2,5-dione (M⁺ +1), 478.51 hydrochloride (M+ − 1). 1533-(Benzofur-7-yl)-4-[1-(4-trans-pyrrolidin-1- MS(ES, m/z) 480.42ylcyclohexyl)-1H-indol-3-yl]pyrrole-2,5-dione (M⁺ + 1), 478.53hydrochloride (M⁺ − 1). 1543-(6-Fluorobenzofur-7-yl)-4-[1-(1-isopropylpiperidin- ES(M⁺ + H): 472.24-yl)-1H-indol-3-yl]pyrrole-2,5-dione 1553-(Benzofur-7-yl)-4-[1-(4-trans-sec- MS(ES, m/z) 500.31butylaminocyclohexyl)-4-fluoro-1H-indol-3- (M⁺ + 1), 498.46yl]pyrrole-2,5-dione hydrochloride (M⁺ − 1).

EXAMPLE 156 Cis and Trans3-(6-Fluorobenzofur-7-yl)-4-[1-(4-hydroxycyclohexyl)-1H-indol-3-yl]pyrrole-2,5-dione

Cool a solution of3-(6-fluorobenzofur-7-yl)-4-[1-(4-oxocyclohexyl)-1H-indol-3-yl]pyrrole-2,5-dione(395 mg, 0.89 mmol) in tetrahydrofuran (20 ml) in an ice bath. Addsodium borohydride (10 mg, 0.27 mmol) in one portion and stir for 5minutes. Add another portion of sodium borohydride (10 mg, 0.27 mmol)and stir for 10 minutes in the ice bath. Quench the reaction is withwater, then dilute with ethyl acetate, wash with water, 1N HCl, brine,dry over magnesium sulfate, filter, concentrate to a red foam.Purification by flash chromatography separates cis and trans isomers togive cis3-(6-fluorobenzofur-7-yl)-4-[1-(4-hydroxycyclohexyl)-1H-indol-3-yl]pyrrole-2,5-dioneand trans3-(6-fluorobenzofur-7-yl)-4-[1-(4-hydroxycyclohexyl)-1H-indol-3-yl]pyrrole-2,5-dioneas red solids. ES(M⁺+H): 445.1.

EXAMPLE 1573-[5-(2-Diethylaminoethoxy)benzofur-7-yl]-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dionehydrochloride

Add to a stirred solution of3-[5-(2-diethylaminoethoxy)benzofur-7-yl]4-(1-methyl-1H-indol-3-yl)furo-2,5-dione(490 mg, 1.07 mmol) in N,N-dimethylformamide (20 ml), methanol (0.2 ml)and 1,1,1,3,3,3-hexamethyl-disilazane (2.25 ml, 10.7 mmol). Heat thereaction to 60° C. overnight. Reaction is continued over the followingtwo nights, along with further additions of1,1,1,3,3,3-hexamethyl-disilazane (3×1 ml), until reaction is complete.Diluted with ethyl acetate, wash with water, brine, dry over sodiumsulfate, filter and concentrate to a red oil. Reversed phasechromatography (acetonitrile: 0.1% hydrochloric acid/H₂O) affords theproduct as an orange solid. Trituration from 5% methanol:dichloromethanewith diethyl ether, then filtration, gives the title compound (230 mg,43%) as an orange solid. EMS: calculated 458.2080 found 458.2069.

Using the method described above, the following compounds are made in asubstantially similar manner: EXAMPLE # Product Physical Data 1583-[4-(2-Diethylaminoethoxy)benzofur- HRMS(M + 1):7-yl]-4-(1-iso-propyl-1H-indol-3- 486.2408 yl)pyrrole-2,5-dionehydrochloride 159 3-[4-(2-Diethylaminopropoxy)benzofur-7- HRMS(M + 1):yl]-4-(1-iso-propyl-1H-indol-3-yl)pyrrole- 500.2552 2,5-dionehydrochloride 160 3-(5-Aminobenzofur-7-yl)-4-(1-methyl- HRMS(M + 1):1H-indol-3-yl)pyrrole-2,5-dione 358.1196. 1613-[4-(N-acetamide)benzofur-7-yl)-4-(1- ES(M⁺ + 1)methyl-1H-indol-3-yl)pyrrole-2,5-dione 400.1

EXAMPLE 1623-Imidazo[1,2-a]pyridin-3-yl)-4-{1-[1-(N,N-dimethylacetamide)piperidin-4-yl]indol-3-yl}pyrrole-2,5-dione

Dissolve3-imidazo[1,2-a]pyridin-3-yl-4-[1-(piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dionehydrochloride (200 mg, 0.45 mmol) in methanol (2 ml). Add triethylamine(0.19 ml, 1.34 mmol), followed by N,N-dimethyl carbamyl chloride (0.06ml, 0.67 mmol) and stir under nitrogen atmosphere for one hour.Concentrate to a red oil. Purification by flash chromatography (ethylacetate) yields 180 mg (83%) of the title compound as an orange solid.ES(M⁺¹): 483.2

The following compounds may be prepared essentially as described above:EXAMPLE # Product Name Physical Data 1633-(Imidazo[1,2-a]pyridin-3-yl)-4-{5-chloro-1-[3,3- ES (M ++ H):dimethyl-1-(N,N-dimethylacetamide)piperidin-4- 545.1yl]indol-3-yl}pyrrole-2,5-dione 1643-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-{1-[1-(2- MSdimethylamino-1-oxoethyl)piperidin-4-yl]-1H-indol-3- 517 (M + H)yl}pyrrole-2,5-dione 1653-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-{1-[1-(N,N- MS (M + H) 503dimethylacetamide)piperidin-4-yl]-1H-indol-3- yl}pyrrole-2,5-dione

EXAMPLE 1663-(Imidazo[1,2-a]pyridin-3-yl)-4-[1-(1-propionylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione

Dissolve3-(imidazo[1,2-a]pyridin-3-yl)-4-[1-(piperidin-4-yl)-1H-indol-3-yl]-pyrrole-2,5-dionehydrochloride (90 mg, 0.22 mmol) and 1.0 M hydrochloric acid in 10 mL8:2 methanol:distilled water. Add propionic anhydride (0.1 mL, 0.078mmol) immediately followed by triethylamine (0.3 mL, 2.1 mmol). Stir thereaction at 20° C. for 30 minutes, filter the solid, rinse with coldmethanol and dry at 70° C. under reduced pressure vacuum to provide thetitle compound. ES(M++H): 468.2.

EXAMPLE 167 3-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-{1-[1-(1-carboxylicacid 2-methoxyethylester)piperidin-4-yl]-1H-indol-3-yl-}-pyrrole-2,5-dione

Add triethyl amine (0.1 mL, 0.7 mmol) and chloroformic acid2-methoxyethyl ester (50 μM, 0.46 mmol) to a solution of3-(6-fluoro-2,3-dihydrobenzofur-7-yl)-4-[1-(piperidin-4-yl)-1H-indol-3-yl]-pyrrole-2,5-dione(100 mg, 0.23 mmol) in methanol (3 mL). Stir the reaction mixture atambient temperature for 2 hours. Dilute with ethyl acetate and wash theorganic layer with water, dry (MgSO₄), concentrate, and chromatograph(silica gel; hexane/EtOAc, 1:1 to 0:1). An orange solid is isolated (55mg, 45%). MS (ESI) m/z 534 (M+H)⁺.

The following compounds may be prepared essentially as described above:EXAMPLE # Product Name Physical Data 1683-(Imidazo[1,2-a]pyridin-3-yl)-4-{1-[1-(1-carboxylic acid MS (M + H)2-propyl)piperidin-4-yl]-1H-indol-3-yl}pyrrole-2,5-dione 498 1693-(Imidazo[1,2-a]pyridin-3-yl)-4-{1-[1-(1-carboxylic acid MS (M + H)2-isopropyl)piperidin-4-yl]-1H-indol-3-yl}pyrrole-2,5- 498 dione

EXAMPLE 1703-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-{1-[1-(pyrazine-2-carbonyl)piperidin-4-yl]-1H-indol-3-yl}pyrrole-2,5-dione

Mix3-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-[1-(piperidin-4-yl]-1H-indol-3-yl)pyrrole-2,5-dione(180 mg, 0.42 mmol) in dimethylformamide with triethyl amine (0.2 mL,1.4 mmol), 2-pyrazinecarboxylic acid (57 mg, 0.46 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimid hydrochloride (106 mg,0.55 mmol), and 1-hydroxybenzotriazole (74 mg, 0.55 mmol). Stir thereaction mixture at ambient temperature for 18 hours. Dilute with ethylacetate, and wash the organic layer with water/brine (×4). Dry overmagnesium sulfate and concentrate. Purify by chromatography (silica gel;hexane/EtOAc; 1:1 to 0:1) to give an orange solid (105 mg, 49%). MS(MSI) m/z 538 (M+H)⁺.

The following compounds are prepared essentially as described above:EXAMPLE # Product Name Physical Data 1713-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-{1-[1- MS (M + H) 537(pyridine-2-carbonyl)piperidin-4-yl]-1H-indol-3- yl}pyrrole-2,5-dione172 3-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-{1-[1- MS (M + H) 537(pyridine-3-carbonyl)piperidin-4-yl]-1H-indol-3- yl}pyrrole-2,5-dione173 3-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-{1-[1- MS (M + H) 538(pyrimidine-5-carbonyl)piperidin-4-yl]-1H-indol- 3-yl}pyrrole-2,5-dione174 3-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-{1-[1- MS (M + H) 537(pyridine-4-carbonyl)piperidin-4-yl]-1H-indol-3- yl}pyrrole-2,5-dione

EXAMPLE 1753-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-[1-(1-methylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione

Beginning with3-(6-fluoro-2,3-dihydrobenzofur-7-yl)-4-{1-[1-(Boc)piperidin-4-yl]-1H-indol-3-yl}pyrrole-2,5-dione,the title compound is prepared essentially as described in Preparation134. MS(M+H)=446.

EXAMPLE 1763-(Imidazo[1,2-a]pyridin-3-yl)-4-[1-(1-isopropylpiperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione

Beginning with3-(imidazo[1,2-a]pyridin-3-yl)-4-{1-[1-(Boc)piperidin-4-yl]-1H-indol-3-yl}pyrrole-2,5-dione,the title compound is prepared essentially as described in Preparation134. MS(M+H)=454.

Kinase Inhibition Assay

An important in vitro test is the ability of the compound to inhibit theactivity of the GSK-3β enzyme. This test is done according to a standardprotocol. (See Fiol, et al, A Secondary Phosphorylation of CREB³⁴¹ atSer¹²⁹ Is Required for the cAMP-Mediated Control of Gene Expression: ARole for Glycogen Synthase Kinase-3 in the Control of Gene Expression,J. Biol. Chem., 269, 32187-32193 (1994)).

The catalysis of the reaction:

KRREILSRRP(pS)YR+AT³³P→KRREIL(³³pS)RRP(pS)YR [measured]+ADP by GSK-3β ismeasured in a reaction mixture comprised of the following: 50 mM MOPS(4-morpholinepropanesulfonic acid) pH 7.0; 50 μM phosphoCREB peptide; 50μM ATP; 0.5 μCi ATP[γ-³³P]; 12.5 mM MgCl₂; 0.03% Triton-X; 4% DMSO; and1 nM recombinant human GSK-3β. The reaction is initiated by the additionof enzyme. The final reaction volume is 100 μL. The reaction is allowedto proceed for 60 minutes at room temperature and is stopped by theaddition of 75 μL of 10% phosphoric acid. To captureKRREIL(³³pS)RRP(pS)YR formed in the reaction and to remove unreactedAT³³P, 160 μL of the stopped reaction mixture is transferred to apre-wetted (0.75% phosphoric acid) phosphocellulose microfiltrationplate [Millipore Cat.# MAPH NOB 50] and after 90 minutes incubation onthe plate, the stopped reaction mixture is passed through the filterusing a Titertek Map Extractor. The filter containing the trappedKRREIL(³³pS)RRP(pS)YR is washed with 220 μL of 0.75% phosphoric acid.Filter plates are blotted to remove droplets from the underdrain. Theunderdrain is removed from the filter and the filter is placed into aclear plate liner (Wallac, Inc.). Added to each well is 100 μL ofMicroscint 20 (Packard).

After standing at least six hours (preferably overnight), the plates arecounted in a Trilux scintillation counter (Wallac, Inc.). The ability ofa compound to inhibit GSK-30 is determined by including variousconcentrations of the compound in the reaction mixture and comparing thesignal produced to the signal produced in a reaction mixture without thecompound.

The test yields the molar concentration of the test compound thatproduces a 50% inhibition of the GSK-3β enzyme activity. The lower thevalue in this test, the more active the test compound is. Theexemplified compounds exhibit IC50≦1 μM.

In the present invention, inhibitors that demonstrate 50% effectiveconcentrations (IC₅₀) of about 200 nM or less are preferred.Furthermore, also preferred are those which show 50% effectiveconcentrations of 50 nM or less, more preferably those which show 50%effective concentrations of 20 nM or less, and most preferably thosewhich show 50% effective concentrations of 10 nM or less in the protocoldescribed by FIOL, Carol J., et al., J. Biol. Chem., 269, 32187-32193(1994). It is also preferred, in the practice of the present invention,that the GSK-3 inhibitor achieve plasma exposures >1000 ng*hr/mL.Additionally, those GSK-3 inhibitors exhibiting a low IC₅₀ value, suchas below 10 nm, and plasma exposures <1000 ng*hr/mL represent a furtherpreferred embodiment of the present invention.

Representative examples are shown in Table II. TABLE II Ex. # GSK-3βIC50 (μM) 1 0.1757 100 0.14341 102 0.1253 114 0.1327 118 0.07019 1190.0095 135 0.0552 139 0.00574 150 0.0106

Glycogen Synthesis Assay

This test measures the increase in the production of glycogen both inthe absence and in the presence of insulin in the cells. This test isdone according to standard protocols. (See Berger and Hayes, AHigh-Capacity assay for Activators of Glucose Incorporation intoGlycogen in L6 Muscle Cells, Analytical Biochemistry. 261, 159-163(1998).)

Briefly, 3T3-L1 adipocytes are plated and differentiated in a 96-wellplate at 25,000 cells/well. The plate is serum-starved overnight. Theserum-starvation media is removed just prior to assay, and the plate iswashed with 100 μl/well Krebs-Ringer-Hepes buffer (KRBH). The KRBH isremoved and 50 μl of compound (twice the amount of the finalconcentration) is added to the assay plate. Next, 50 μl of ¹⁴C-labeledglucose is added to the assay plate at 0.1 μCi/well. The plate is thenincubated at 37° C. for 2 hours.

The plate is washed with 100 μL/well of PBS, and the cells are lysedwith 75 μl/well of 1N NaOH. The plate is heated at 70° C. for 20minutes. An aliquot (50 μl) of the supernatant is transferred from theassay plate to a Millipore FC filter plate containing 120 μl/well ofice-cold ethanol. The plate is allowed to stand for 2 hours at 4° C. tofacilitate precipitation. The ethanol is removed from the filter platevia a vacuum manifold, and the plate is washed with 100 μL/well ofice-cold 70% ethanol. The plate was allowed to dry overnight, and 75μl/well of Microscint-20 was added to the filter plate. The plate wasthen counted on a Packard Topcount.

Glucose Lowering Assay

This test measures the effect of the test compound on blood glucose andtriglycerides relative to insulin. (See Eldar-Finkleman, et al,Expression and Characterization of Glycogen Synthase Kinase-3 Mutantsand Their Effect on Glycogen Synthase Activity in Intact Cells, Proc.Nat. Acad. Sci., 93, 10228-10233 (1996).)

ZDF rats (Charles River, Inc.) at six weeks of age are housedindividually with free access to food and water. Rats are dosed withdrug once daily by oral gavage, with the compound prepared as asuspension in 1% caboxymethylcellusolve/0.25% Tween 80 (CMC-Tween).Vehicle controls are dosed with CMC-Tween only. The duration of studyvaried according to the protocol used, with acute dosing studies lastingone day and dose escalation studies lasting seven days. Body weights andfood consumption measurements are also performed once a week forseven-day studies. For measurement of blood glucose and triglycerides,blood samples of 600 μl are collected by the tail snip method. (The tailsnip for blood sampling is as follows: 1-2 mm of the tail is snippedwith a sharp blade. After collection of blood, a scab forms at the siteof wound. This scab is removed and the tail is gently massaged for othersubsequent bleedings.) Glucose and triglyceride determinations areperformed on a Hitachi 912 metabolic analyzer, with a kit utilizing theTrinder method. On termination of study, specific tissues (e.g., heart,pancreas, adipose tissues, and liver) are excised to evaluate the effectof these drugs on their metabolic functions.

Ex Vivo Brain Assay

This assay assesses the GSK-3β kinase activity of the test compound inbrain cortex tissue. It is performed according to standard protocols(Wang, et al., Anal. Biochem., 220, 397402 (1994)).

The ex vivo GSK-30 kinase activity of a compound is assayed followingoral dosing of 2 to 3 month old PDAPP or CD-1 mice. After a 20 mg/kg, 24hour dose, followed by an additional three-hour dose, brain cortextissue is dissected and homogenized in freshly prepared lysis buffer (10mM K₂HPO₄ pH 7.2, 1 mM EDTA, 5 mM EGTA, 10 mM MgCl₂, 50 mMβ-Glycerophosphate, 1 mM Na₃VO₄, 2 mM DTT, 1 μM Microcystin, COMPLETEprotease inhibitor tablet, no detergent). Following a thirty-minuteincubation on ice, cortex homogenate samples are centrifuged (100,000 G)for 30 minutes at 4° C. The total protein concentration of homogenate isdetermined using the BCA method (Pierce). GSK-3β activity in cytosolichomogenate from vehicle- and compound-treated mice is then assayed. Thekinase reaction occurs in a 50 μl total volume containing 20 mM MOPS pH7.4, 25 mM O-glycerol phosphate, 5 mM EGTA, 1 mM NA₃VO₄, 1 mM DTT, 15 mMMgCl₂, 100 μM cold ATP, 200 μM CREB peptide, 10 μL cytosolic cortexbrain homogenate, and 5 μCi γ-³³P-ATP. The reactions are incubated forthirty minutes at 30° C. using a Costar round-96 polypropylene plate.Reactions are then stopped with, the addition of 10% H₃PO₄ andtransferred to a Millipore MAPH-NOB 96-well phosphocellulose plate.Next, the reaction is incubated at room temperature for 1.5 hours,filtered and washed with 320 μl 0.75% H₃PO₄, and filtered and washedwith 160 μl H₃PO₄ at the same concentration using a vacuum manifold. Thefilter plate is then placed in a carrier plate, and 100 μl of Microscint20 is added to each well. The plate is sealed with sealing tape andincubated overnight at room temperature. The following day, the filterplate is read for ³³P on Top Count (Packard). Finally, CPM is normalizedto CPM per μg of total protein.

β-Catenin Protection Assay

This test measures the fold induction over basal β-catenin and isperformed according to standard protocols (Hedgepeth, C. M., Dev. Biol.185, 82-91 (1997); Chen, G., et al., J. Neurochem., 72, 1327-1330(1999); Hong, M., et al., J. Biol. Chem., 272, 25326-25332 (1997)).

The human familial Alzheimer's disease (FAD) presenilin-1 AG04160Clymphoblast cell line (Coriell Cell Repository, Camden, N.J.) ismaintained as a suspension culture in RPMI 1640 (with L-Glutamine)supplemented with 10% fetal bovine serum and 1% penicillin-streptomycinin an atmosphere of 37° C. and 5% CO₂. The AG04160C FAD lymphoblastcells are seeded in T-25 cm² flasks at 2.5 to 5.0×10⁵ cells/ml in atotal volume of 10 ml. Following 16-18 hours of growth, cells aretreated with compound at concentrations of 0.1 μM, 1.0 μM, and 10 μM,and are incubated for an additional 24 hours. At the completion of the24-hour incubation, cells are harvested, washed with PBS, and lysed infreshly prepared lysis buffer (10 mM K₂HPO₄ pH 7.2, 1 mM EDTA, 5 mMEGTA, 10 mM MgCl₂, 50 mM β-Glycerophosphate, 1 mM Na₃VO₄, 2 mM DTT, 1 μMMicrocystin, 1 mM PMSF, 10 μg/ml leupeptin, 1 μg/ml pepstatin, 1 μg/mlaprotinin, 1% Triton X-100). After a thirty-minute incubation on ice,cells are centrifuged (14,000 rpm) for 30 minutes at 4° C., andresulting supernatants are used as whole cell lysates. The total proteinconcentration in whole cell lysate samples is determined using the BCAmethod (Pierce). Next, 15 μg of sample is loaded on a 10% Bis-TrisNuPage gel and transferred to a pure nitrocellulose membrane followed byβ-catenin immunoblot analysis using a β-catenin specific antibody(Transduction Labs). The β-catenin accumulation/stability is thenquantified following densitometry analysis of protein bands. Finalresults are reported as fold induction over basal β-catenin.

Representative examples are shown in Table III. TABLE III GlycogenSynthesis Glucose Lowering β-Catenin GSK-3β IC50 (fold increase at(percent increase vs. (fold Ex. # (μM)) 1 μM) effect of insulin)increase) 119 0.0095 2.82× in absence of 4.9X insulin 2.13× in presenceof insulin 150 0.0106 2.97× in absence of 58% insulin 3.92× in presenceof insulin

Ovariectomized Rat Assay

Six-month-old virgin Sprague-Dawley rats are maintained on a 12-hourlight, 12-hour dark cycle at 22° C. with ad libitum access to food(TD89222 with 0.5% calcium and 0.4% phosphate, Teklad, Madison, Wis.)and water. Bilateral or sham ovariectomies are performed on the rats andthey are allowed to lose bone for 1 month. When the rats are 7 monthsold, sham and ovariectomized (Ovx) controls (7 animals per group) areorally administered vehicle (1% carboxymethyl cellulose/0.25% Tween 80)and a second group of 7 Ovx animals is orally administered the testcompound in vehicle. Dosing is done once a day for 2 months. At the endof 2 months, rats are euthanized using CO₂ anesthesia and left femur andvertebra are removed, cleaned of soft tissue and stored in 50%ethanol/saline. Bones are analyzed by QCT as described previously (SatoM., Comparative x-ray densitometry of bones from ovariectomized rats.Bone 17:157S:162S (1995); Sato M., Kim J., Short L. L., Slemenda C. W,Bryant H. U., Longitudinal and cross-sectional analysis of raloxifeneeffects on tibiae from ovariectomized aged rats. J Pharmacol Exp Ther272:1252-1259 (1995)).

Compounds of Formula I may be administered by the oral, transdermal,percutaneous, intravenous, intramuscular, intranasal or intrarectalroute, in particular circumstances. The route of administration may bevaried in any way, limited by the physical properties of the drugs, theconvenience of the patient and the caregiver, and other relevantcircumstances (See Remington's Pharmaceutical Sciences, 18 h Ed., MackPublishing Co. (1990).)

The pharmaceutical compositions are prepared in a manner well known inthe pharmaceutical art. The carrier or excipient may be a solid,semi-solid, or liquid material which can serve as a vehicle or mediumfor the active ingredient. Suitable carriers or excipients are wellknown in the art. The pharmaceutical composition may be adapted fororal, inhalation, parenteral, or topical use and may be administered tothe patient in the form of tablets, capsules, aerosols, inhalants,suppositories, solutions, suspensions, or the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or capsules or compressed into tablets.For the purpose of oral therapeutic administration, the compounds may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gums and thelike. These preparations should contain at least 4% of the compound ofthe present invention, the active ingredient, but may be varieddepending upon the particular form and may conveniently be between 4% toabout 70% of the weight of the unit. The amount of the compound presentin compositions is such that a suitable dosage will be obtained.Preferred compositions and preparations according to the presentinvention may be determined by a person skilled in the art.

The tablets, pills, capsules, troches, and the like may also contain oneor more of the following adjuvants: binders such as microcrystallinecellulose, gum tragacanth or gelatin; excipients such as starch orlactose, disintegrating agents such as alginic acid, Primogel, cornstarch and the like; lubricants such as magnesium stearate or Sterotex;glidants such as colloidal silicon dioxide; and sweetening agents suchas sucrose or saccharin may be added or a flavoring agent such aspeppermint, methyl salicylate or orange flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol or a fatty oil. Otherdosage unit forms may contain other various materials that modify thephysical form of the dosage unit, for example, as coatings. Thus,tablets or pills may be coated with sugar, shellac, or other coatingagents. A syrup may contain, in addition to the present compounds,sucrose as a sweetening agent and certain preservatives, dyes andcolorings and flavors. Materials used in preparing these variouscompositions should be pharmaceutically pure and non-toxic in theamounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations typically contain at least 0.1% of acompound of the invention, but may be varied to be between 0.1 and about90% of the weight thereof. The amount of the compound of Formula Ipresent in such compositions is such that a suitable dosage will beobtained. The solutions or suspensions may also include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl paraben; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylene diaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic. Preferred compositionsand preparations are able to be determined by one skilled in the art.

The compounds of the present invention may also be administeredtopically, and when done so the carrier may suitably comprise asolution, ointment, or gel base. The base, for example, may comprise oneor more of the following: petrolatum, lanolin, polyethylene glycols,bees wax, mineral oil, diluents such as water and alcohol, andemulsifiers, and stabilizers. Topical formulations may contain aconcentration of the Formula I, or its pharmaceutical salt, from about0.1 to about 10% w/v (weight per unit volume).

The compounds of Formula I are generally effective over a wide dosagerange. For example, dosages per day normally fall within the range ofabout 0.0001 to about 30 mg/kg of body weight. In some instances dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, and therefore the above dosagerange is not intended to limit the scope of the invention in any way. Itwill be understood that the amount of the compound actually administeredwill be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound or compounds administered, theage, weight, and response of the individual patient, and the severity ofthe patient's symptoms.

1. A compound of Formula I

where: Ar is benzofur-7-yl optionally substituted in the phenyl ringwith R⁸ and R⁹, 1-(R⁷)-indol-4-yl, benzofur-4-yl, quinolin-5-yl,quinolin-7-yl, isoquinolin-5-yl, isoquinolin-3-yl,imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl,furo[3,2-c]pyridin-7-yl, benzo[1,3]dioxol-4-yl,2,2-difluorobenzo[1,3]dioxol-4-yl, or 2,3-dihydrobenzofur-7-yloptionally substituted in the phenyl ring with R⁸ and R⁹ and in thedihydrofuryl ring with C₁-C₄ alkyl; R^(1a) is hydrogen, C₁-C₄ alkoxy,—(CH₂)_(m)-G, —O—(CH₂)_(m)-G, halo, C₁-C₄ alkyl optionally substitutedwith one to three halo, piperazin-1-yl optionally substituted 1-2 timeswith —(CO₂)_(n)—(C₁-C₄ alkyl), or —(CH₂)—O—(CH₂)—O—(CH₃); R^(1b) ishydrogen or halo; R^(1c) is hydrogen or halo; G is independently at eachoccurrence hydroxy, NR¹¹R¹², or piperidin-4-yl; R² is hydrogen, C₁-C₄alkyl, —(CH₂)_(m)-G, tetrahydropyran-4-yl, 4-(NR⁴R⁵)cyclo-hex-1-yl,4-hydroxycyclohex-1-yl, 2-azabicyclo[3.2.1]oct-5-yl, the moiety

 the moiety

 cyclohexan-1-on-4-yl, pyridin-4-yl; and R³ is hydrogen, halo, C₁-C₄alkyl, or cyclopropyl; or R² and R³ taken together represent

R⁴ is hydrogen and R⁵ is hydrogen or C₁-C₄ alkyl, or R⁴ and R⁵ takentogether with nitrogen to which they are attached form a pyrrolidinering; R⁶ is hydrogen, benzyl, —CO₂(C₁-C₄ alkyl), —C(O)—(C₁-C₄alkyl)_(n)—NR¹⁴R¹⁵, —C(O)tetrahydropyran-4-yl, —C(O)morpholin-4-yl,—CH₂-tetrahydropyran-4-yl, an amino acid residue, —C(O)pyridin-2-yl,—C(O)pyridin-3-yl, —C(O)pyridin-4-yl, —C(O)pyrimidin-5-yl, C₁-C₄ alkyl,—C(O)pyrazin-2-yl, or —CO₂—(C₁-C₄ alkyl)-(C₁-C₄ alkoxy); R⁷ is hydrogen,C₁-C₄ alkyl, or —(CH₂)_(m)-G; R⁸ is —NHCO₂(C₁-C₄ alkyl), —NHSO₂(C₁-C₄alkyl), halo, amino, —O—(CH₂)_(m)-G, —NHC(O)(C₁-C₄ alkyl), C₁-C₄ alkoxy,hydroxy, —O—R¹⁰, C₁-C₄ alkyl, C₁-C₄ alkylthio, or —(CH₂)_(m)-G; R⁹ ishalo; R¹⁰ is piperidin-3-yl, piperidin-4-yl, or pyrrolidin-3-yl; R¹¹ andR¹² are independently selected from the group consisting of hydrogen,C₁-C₄ alkyl, cyclopropylmethyl, benzyl, or, taken together with thenitrogen to which they are attached form a piperidine,4-hydroxypiperidine, 4-(C₁-C₄ alkyl)piperidine, N—(R¹³)-piperazine, ormorpholine ring; R¹³ is hydrogen, C(O)—(C₁-C₄ alkyl), or C₁-C₄ alkyl;R¹⁴ and R¹⁵ are independently hydrogen or C₁-C₄ alkyl; R¹⁶ isindependently at each occurrence hydrogen, geminal dimethyl, geminaldiethyl, a spiro-fused C₃-C₆ cycloalkyl, or C₁-C₄ alkyl optionallysubstituted with hydroxy; and R¹⁷ represents hydrogen, C₁-C₄ alkyl, orgeminal dimethyl, provided that the total number of carbon atoms betweenR¹⁶ and R¹⁷ does not exceed five; m is independently at each occurrence2, 3, 4, or 5; n is independently at each occurrence 0 or 1; or apharmaceutically acceptable salt thereof, subject to the followingprovisos: i) when G is hydroxy, no more than two of R^(1a), R², R⁷, orR⁸ may be —(CH₂)_(m)-G, or —O—(CH₂)_(m)-G; and ii) when G is NR¹¹R¹², nomore than one of R^(1a), R², R⁷, or R⁸ may be —(CH₂)_(m)-G, or—O—(CH₂)_(m)-G.
 2. A compound of claim 1 where Ar is benzofur-7-yloptionally substituted in the phenyl ring with R⁸ and R⁹.
 3. A compoundof claim 1 where Ar is 2,3-dihydrobenzofur-7-yl optionally substitutedin the phenyl ring with halo.
 4. A compound of any of claims 1, 2, or 3where R² is


5. A compound of claim 4 where R⁶ is —C(O)morpholin-4-yl or—C(O)pyrazin-2-yl.
 6. A method of treating diabetes in a mammalcomprising administering to a mammal in need of such treatment aneffective amount of a compound of claim
 1. 7. A method of treatingAlzheimer's disease in a mammal comprising administering to a mammal inneed of such treatment an effective amount of a compound of claim
 1. 8.A method for inhibiting GSK-3 in a mammal comprising administering to amammal in need of said inhibition an effective amount of a compound ofclaim
 1. 9. A pharmaceutical formulation comprising a compound of claim1 in combination with a pharmaceutically acceptable carrier, diluent, orexcipient.
 10. A method of stimulating bone deposition in a mammalcomprising administering to a mammal in need of such treatment aneffective amount of a compound of claim 1.